ES2834065T3 - Arginase inhibitors and their therapeutic applications - Google Patents

Abstract

A compound represented by Formula (Ib): ** (See formula) ** wherein: R 'is -OH, (C1-C8) alkyl or -NH2, wherein the alkyl is optionally substituted with -NRdRe or heterocyclyl which has 3 to 7 atoms as ring members; wherein Rd and Re are each independently hydrogen, straight or branched (C1-C6) alkyl, optionally substituted aryl (C3-C14) alkylene (C1-C6) or optionally substituted (C3-C14) aryl, or a tautomer, stereoisomer , racemate, salt, ester, solvate or pharmaceutically acceptable polymorph thereof.

Description

DESCRIPTION

Arginase inhibitors and their therapeutic applications

Background of the invention

Cross reference to related requests

This application claims priority to US Provisional Application No. 62 / 331,550, filed May 4, 2016, Polish Application No. P-417066, filed May 4, 2016, and US Provisional Application No. USA No.

62 / 444.669, filed on January 10, 2017.

Field of the invention

The description refers to therapeutic inhibitors that are small molecules of arginase 1 and arginase 2.

Description of Related Art

In mammals there are two arginase isozymes (ARG-1 and ARG-2, also called arginase I and II, respectively), which hydrolyze arginine to ornithine and urea. Both enzymes catalyze the same biochemical reaction, but differ in the level of cellular expression, regulation, and subcellular location. ARG-1 is a cytosolic protein and ARG-2 is located mainly in the mitochondria (Jenkinson CP, Grody WW, Cederbaum SD. Comparative properties of arginases. Comparative biochemistry and physiology Part B, Biochemistry & Molecular Biology. 1996; 114 (1) : 107-132).

Arginases are involved in various disease states. These include, without limitation, asthma, pulmonary hypertension, hypertension, T-cell dysfunction, erectile dysfunction, atherosclerosis, kidney disease, ischemic reperfusion injury, neurodegenerative diseases, wound healing, inflammatory diseases, fibrotic diseases, and cancer.

Arginase expression and L-arginine depletion is a known immunosuppressive pathway of the mammalian immune system (Munder M. Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol.

2009; 158 (3): 638-651). L-arginine deficiency down-regulates the expression of the T-cell receptor (TCR) Z chain, a key element of TCR signaling, impairing T-cell function (Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa CA Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem. 2002; 277 (24): 21123-21129). Depletion of L-arginine from the microenvironment leads to an arrest of T cell cycle progression, inhibition of IFN-y production, and blocking of signaling through the T cell receptor.

Arginases are produced primarily by myeloid-derived suppressor cells (MDSCs) that are highly enriched in the tumor-presenting state (Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP, Zanovello P: IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J Immunol 2003; 170: 270-278). Induction of the arginase pathway is an important mechanism involved in evasion of antitumor immunity. High arginase activity has been observed in patients with various neoplasms, both in the blood and within the tumor mass.

It was shown that T cell functions are restored and tumor growth is inhibited after inhibition of MDSC arginase associated with tumors or infiltrating mature myeloid cells of CD11b + Gr-1 tumors in various models of murine tumors (Rodriguez PC, Quiceno DG, Zabaleta J, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004; 64 (16): 5839-5849). Myeloid suppressor cell depletion restores T cell receptor-induced T cell activation and costimulation (Zea AH, Rodriguez PC, Atkins MB, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005; 65 (8): 3044-3048).

Arginase was shown to participate in the suppression of tumor infiltrating lymphocytes in patients with prostate carcinoma (Bronte V, Kasic T, Gri G, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. 2005; 201 (8): 1257-1268), non-small cell lung carcinoma (Rodriguez PC, Quiceno DG, Zabaleta J, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen- specific T-cell responses. Cancer Res. 2004; 64 (16): 5839-5849) and multiple myeloma (Serafini P, Meckel K, Kelso M, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006; 203 (12): 2691-2702). Not only MDSCs but also dendritic cells (DC) have been shown to suppress CD8 + T cells and anti-tumor immune responses through the production of ARG-1 (Norian LA, Rodriguez PC, O'Mara LA, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8 + T cell function via L-arginine metabolism. Cancer Res. 2009; 69 (7): 3086-3094).

Given the role of arginase in various disease states and its role in chronic inflammation and suppression of antitumor immunity, the present invention provides novel boron-containing compounds as inhibitors of arginase activity, as well as methodologies for using these compounds as agents. therapeutic.

Numerous boron-containing arginase inhibitors are well known in the literature. One of these inhibitors is 2 (S) -amino-6-boronohexanoic acid, as described in WO 99 / 19295A1, published April 22, 1999 and in WO 08 / 061612A1, published May 29, 2008. Furthermore , WO 11/133653, published October 27, 2011 and WO 13/059437, published April 25, 2013, describe a series of alpha-amino acid derivatives that carry a terminal B (OH) 2 group and a spacer, which is usually a 1,3-cyclobutylene residue. Suitable boron-containing mono or polycyclic amino acid compounds as arginase inhibitors are described in WO 12/058065, published May 3, 2012. Other related patent application publications are WO 10/085797 of July 29, 2010 , Wo 13/158262 of October 24, 2013 and WO 12/091757 of June 5, 2012. A boronated derivative of 1-aminocyclobutanecarboxylic acid similar to the compounds of the present invention is known (Kabalka GW and Yao M.-L Synthesis of a novel boronated 1-aminocyclobutanecarboxylic acid as a potential boron neutron capture therapy agent, Appl. Organometal. Chem., 2003, 17, 398-402). Boronated unnatural cyclic amino acids are known in the art as therapeutic agents for the treatment of cancer (Kabalka GW et al., Synthesis of a series of boronated unnatural cyclic amino acids as potential boron neutron capture therapy agents, Appl. Organometal. Chem. 2008, 22, 516-522).

The significance of substitution at the alpha center of 2-amino-6-boronohecanoic acid for the inhibitory potency of arginase I and arginase II inhibitors has been discussed (Golebiowski A., et al. 2-Substituted-2- amino-6-boronohexanoic acids as arginase inhibitors. Bioorg. & Med. Chem. Lett., 2013; 23: 2027-2030).

There is a need to investigate arginase inhibition and discover treatments for conditions associated with elevated arginase expression, such as asthma and allergic responses. In particular, there is a need to explore new molecular scaffolds that effectively inhibit arginases and therefore can act as therapeutic agents for the treatment of these conditions.

Summary of the invention

In one aspect, the invention provides a compound represented by Formula (Ib):

where:

R 'is -OH, (C ¹ -C ⁸ ) alkyl, or -NH ² , wherein the alkyl is optionally substituted with -NR ^d R ^e or heterocyclyl having 3 to 7 atoms as ring members;

wherein R ^d and R ^e are each independently hydrogen, straight or branched ^{(C 1} -C ^{6) alkyl,}

aryl (C ³ -C ¹⁴ ) optionally substituted (C ¹ -C ⁶ ) alkylene or optionally substituted (C ³ -C ¹⁴ ) aryl,

or a pharmaceutically acceptable tautomer, stereoisomer, racemate, salt, ester, solvate, or polymorph thereof. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable stereoisomer, tautomer, salt or solvate thereof, and a pharmaceutically acceptable carrier.

The compound according to claim 1, or a pharmaceutically acceptable stereoisomer, tautomer, salt or solvate thereof, for use in the treatment or prevention of a disease or condition selected from the group consisting of cardiovascular disorders, sexual disorders, healing disorders of wounds, gastrointestinal disorders. autoimmune disorders, immune disorders, infections, lung disorders, hemolytic disorders, and cancers.

Detailed description

The present invention is based on a surprising discovery that some small molecule arginase inhibitors possess very high activity accompanied by superior pharmacokinetics.

Definitions

The articles "a" and "an" are used herein to refer to one or more than one (ie, at least one) of the article's grammatical object. By way of example, "an item" means one item or more than one item.

The terms used herein may be preceded and / or followed by a single dash "-" or a double dash "=", to indicate the bond order of the bond between the mentioned substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety; furthermore, substituents are intended to be read "from left to right", unless a hyphen indicates otherwise. For example, (C ¹ -C ⁶ ) alkoxycarbonyloxy and -OC (O) O (C ¹ -C ⁶ )alkyl indicate the same functionality; similarly, arylalkyl and alkylaryl indicate the same functionality.

The term "heteroatom" is recognized in the art and refers to an atom of any element other than carbon or hydrogen. Illustrative examples of heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium.

The term "alkyl" as used herein is a term of the art and refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, substituted cycloalkyl groups with alkyl and cycloalkyl substituted alkyl groups. In some embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its structure (eg, C ¹ -C ³⁰ for straight chains, C ³ -C ³⁰ for branched chains), and alternatively about 20 or less, 10 or less, or preferably 1-6 carbons. Representative examples of alkyl include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term "cycloalkyl" means saturated or partially saturated mono or bicyclic or bridged carbocyclic rings, each of which has 3 to 12 carbon atoms. Certain cycloalkyls have 3-8 or 3-6 carbon atoms in their ring structure. Certain cycloalkyls have 5-12 carbon atoms in their ring structure, and can have 6-10 carbons in their ring structure. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Monocyclic bridged rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form - (CH ² ) ^w -, where w is 1,2 or 3). Representative examples of bicyclic ring systems include, for example, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1 ] nonane, and bicyclo [4.2.1] nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted.In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused with a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

The term "heterocyclyl" as used herein refers to a radical of a non-aromatic ring system, including, for example, monocyclic, bicyclic, and tricyclic rings, which may be fully saturated or may contain one or more unsaturation units, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and has 3 to 14, or 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. The most preferred heterocycloalkyl groups have 5-10 ring members, where 1-4 of the ring members are heteroatoms selected from the group consisting of O, N, and S, with the remaining ring atoms being C. For purposes of For exemplification, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiranyl, tyrenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,

1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azethyl, oxethanyl, oxethyl, thietanyl, thiethyl, diazetidinyl, dioxetanil, dioxetenyl, oxiazolidinyl, pyroliazolidinyl, pyroliazolidinyl, dithiexalanyl, pyridiazolidyl, tiazolidinyl, dithiexalanyl, pyrolithiazolidinyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazopyridazolinyl, benzozolothiazolinyl, benzoiazolinyl, pyridozolothyl, quinazopyidazolinyl, indolyl, benztriazolyl, naphthyridinyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxypyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, tetrahydrofopyranyl, pyrazolinyl, pyroliduranyl, pyrazolidurolidinyl, pyrazolidurolidinyl, pyrazolidinyl, pyrazolidrofoxy lo, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxydothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. A heterocyclyl group is optionally substituted with one or more substituents as described below.

As used herein, the term "heterocyclylene" refers to a bivalent heterocyclyl (heterocycloalkyl) group, that is, a cyclic alkylene group, having 3-10 members and 1-4 heteroatoms. selected from S, O and N. An example is piperidine-2,3-dicarboxylic acid, that is, in this compound, the piperidine ring is a heterocyclyl group.

The term "heteroatom" is recognized in the art and includes an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, and alternatively oxygen, nitrogen, or sulfur.

The term "cycloalkylalkyl" as used herein refers to an alkyl group substituted with one or more cycloalkyl groups.

The term "heterocycloalkylalkyl" as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

The term "alkenyl", as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the elimination of two hydrogens. . Representative examples of alkenyl include, for example, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3 -decenyl. The unsaturated bond or bonds of the alkenyl group can be located anywhere in the rest and can have the (Z) or (E) configuration around the bond or double bonds.

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,

2-pentynyl and 1-butynyl.

The term "alkylene" is recognized in the art and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from an alkyl group, as defined above. In one embodiment, an alkylene refers to a disubstituted alkane, that is, an alkane substituted in two positions with substituents such as, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano. That is, in one embodiment, a "substituted alkyl" is an "alkylene."

The term "amino" is an art term and, as used herein, refers to substituted and unsubstituted amines, eg. eg, a remainder that can be represented by the general formulas:

wherein R ^a , R ^b, and R ^c each independently represent a hydrogen, an alkyl, an alkenyl, - (CH ² ) ^x -R ^d, or R ^a and R ^b, taken together with the N atom to which they are attached to complete a heterocycle having 4 to 8 atoms in the ring structure; R ^d represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range 1 to 8. In certain embodiments, only one of R ^a or R ^b can be a carbonyl, e.g. eg, R ^a , R ^b, and nitrogen together do not form an imide. In other embodiments, R ^a and R ^b (and optionally R ^c ) each independently represent a hydrogen, an alkyl, an alkenyl, or - (CH ² ) ^x -R ^d .

In certain embodiments, the term "amino" refers to -NH ² .

The term "amido" as used herein means -NHC (= O) -, where the amido group is attached to the parent molecular moiety through nitrogen. Examples of the amido include alkylamido such as CH ^to C (= O) N (H) - and CH ^to CH ² C (= O) N (H) -.

The term "acyl" is a term of the art and as used herein refers to any group or radical of the form RCO- where R is any organic group, e.g. eg, alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

The term "aminoalkyl" as used herein refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

The term "aminoacyl" is an art term and as used herein refers to an acyl group substituted with one or more amino groups.

The term "aminothionyl" as used herein refers to an analog of an aminoacyl in which the O of RC (O) - has been replaced by sulfur, therefore it has the form RC ( S) -.

The term "phosphoryl" is an art term and, as used herein, can be generally represented by the Formula:

Q50

-------- P II --------

OR59

wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl, or an aryl; for example, -P (O) (OMe) -o

-P (O) (OH) 2. When used to substitute, p. For example, an alkyl, the phosphoryl group of phosphorylalkyl can be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S, or N; for example, -OP (O) (OH) OMe or -NH-P (O) (OH) 2. When Q50 is S, the phosphoryl moiety is a "phosphorothioate".

The term "aminophosphoryl" as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P (O) (OH) NMe2.

The term "azide" or "azido", as used herein, means an -N3 group.

The term "carbonyl" as used herein refers to -C (O) -.

The term "thiocarbonyl" as used herein refers to -C (= S) -.

The term "alkylphosphoryl" as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P (O) (OH) Me.

The term "alkylthio" as used herein refers to alkyl-S-.

The term "carboxy" as used herein means a -CO2H group.

The term "aryl" is an art term and as used herein refers to including monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, eg, benzene, naphthalene, anthracene, 1,2,3, 4-tetrahydronaphthalene, indene, 2,3-dihydroindene and pyrene. The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, (cycloalkyl) alkoxy, hydroxy, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, aminosulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, heterocyclylalkyl, aromatic or heteroaromatic moieties, aminoalkyl, fluoroalkyl, haloalkyl, fluoroalkyl, aromatic or heteroaromatic moieties (such as trifluoromethyl), haloalkoxy, cyano. The term "aryl" also includes polycyclic ring systems that have two or more cyclic rings where two or more carbons are common to two contiguous rings (the rings are "fused rings") where at least one of the rings is an aromatic hydrocarbon. , p. For example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkyls, aryls, heteroaryls, and / or heterocyclyls. Representative examples of polycyclic aryl ring systems include, for example, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindole- 4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3- yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6, 7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo [d] [1,3] dioxol-4-yl, benzo [d] [1,3] dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on- 6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindolin-1,3-dion-4-yl, isoindolin-1,3-dion-5- yl, inden-1-on-4-yl, inden-1-on-5-yl, inden-1-on-6-yl, inden-1-on-6-yl, 2,3-dihydrobenzo [b] [1,4] dioxan-5-yl,

2,3-dihydrobenzo [b] [1,4] dioxan-6-yl, 2H-benzo [b] [1,4] oxazin3 (4H) -on-5-yl, 2H-benzo [b] [1, 4] oxazin3 (4H) -on-6-yl, 2H-benzo [b] [1,4] oxazin3 (4H) -on-7-yl, 2H-benzo [b] [1,4] oxazin3 (4H) -on-8-yl, benzo [d] oxazin- 2 (3H) -on-5-yl, benzo [d] oxazin-2 (3H) -on-6-yl, benzo [d] oxazin-2 (3H) -on-7-yl, benzo [d] oxazin -2 (3H) -on-8-yl, quinazolin-4 (3H) -on-5-yl, quinazolin-4 (3H) -on-6-yl, quinazolin-4 (3H) -on-7-yl , quinazolin-4 (3H) -on-8-yl, quinoxalin-2 (1H) -on-5-yl, quinoxalin-2 (1H) -on-6-yl, quinoxalin-2 (1H) -on-7 -yl, quinoxalin-2 (1H) -on-8-yl, benzo [d] thiazol-2 (3H) -on-4-yl, benzo [d] thiazol-2 (3H) -on-5-yl, benzo [d] thiazol-2 (3H) -on-6-yl, and, benzo [d] thiazol-2 (3H) -on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl, or (ii) a phenyl ring fused to a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, or a 5- or 6-membered monocyclic heterocyclyl. , wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted. In certain embodiments, the term "aryl" refers to a phenyl group.

The term "heteroaryl" is an art term and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 14, 5 to 14, or 3 to 12 atoms in total including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Most preferred heteroaryl groups have 5-10 ring members where 1-4 of the ring members are heteroatoms selected from the group consisting of O, N, and S. Exemplary heteroaryl groups include, for example, azaindolyl, benzo ( b) thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, oxadolinyl, pyrazolyl, isothiazolyl, oxadolinyl, purzolinyl, isothiazolyl, oxadolinyl, purzolinylo, isothiazolyl pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo [2,3-d] pyrimidinyl, pyrazolo [3,4-d] pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl or tronyl. The "heteroaryl" may be substituted at one or more ring positions with one or more substituents, such as, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano. The term "heteroaryl" also includes polycyclic ring systems that have two or more cyclic rings where two or more carbons are common to two contiguous rings (the rings are "fused rings"), where at least one of the rings is a aromatic group having one or more heteroatoms in the ring structure, e.g. For example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkyls, aryls, heteroaryls, and / or heterocyclyls. Representative examples of bicyclic heteroaryl include, for example, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, indolylpyridinyl, indazolidinyl, , isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl,

5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl,

4,5,6,7-tetrahydrobenzo [c] [1,2,5] oxadiazolyl, and 6,7-dihydrobenzo [c] [1,2,5] oxadiazol-4 (5H) -onyl. Any heteroaryl or bicyclic heteroaryl can be optionally substituted as detailed below.

The term "aralkyl", "arylalkyl" or "arylalkyl (C1-C6)" is a term of the art and, as used herein, refers to an alkyl group, for example, a C1 alkyl group. -C6, substituted with an aryl group, where the remainder is attached to the parent molecule through the alkyl group.

The term "heteroaralkyl", "heteroarylalkyl" or "heteroarylalkyl (C1-C6)" is a term of the art and as used herein refers to an alkyl group, for example, a C1-C6 alkyl group. , substituted with a heteroaryl group, attached to the parent molecular moiety through the alkyl group.

The term "alkoxy" or "alkoxy", as used herein, means an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, for example, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "alkoxycarbonyl" means an alkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, represented by -C (= O) -, as defined herein. Representative examples of alkoxycarbonyl include, for example, methoxycarbonyl, ethoxycarbonyl, and tert- butoxycarbonyl.

The term "alkylcarbonyl" as used herein means an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, for example, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl,

1-oxobutyl and 1-oxopentyl.

The term "arylcarbonyl" as used herein means an aryl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, for example, benzoyl and (2-pyridinyl) carbonyl.

The term "alkylcarbonyloxy" and "arylcarbonyloxy" as used herein means an alkylcarbonyl or arylcarbonyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, for example, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, for example, phenylcarbonyloxy.

The term "alkenoxy" or "alkenoxy" means an alkenyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxy include, for example, 2-propene-1-oxyl (ie, CH ² = CH-CH ² -O-) and vinyloxy (ie, CH ² = CH-O-).

The term "aryloxy" as used herein means an aryl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.

The term "heteroaryloxy" as used herein means a heteroaryl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.

The term "carbocyclyl" as used herein means a monocyclic or multicyclic (eg, bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms that is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic (eg, phenyl) ring system. Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

The terms "cyano" and "nitrile" is an art term and, as used herein, refers to -CN.

The term "nitro" as used herein means -NO ² .

The term "halo" is an art term and as used herein refers to -F, -Cl, -Br, or -I.

The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, where some or all of the hydrogens are replaced with halogen atoms. The term "haloalkoxy" refers to an alkoxy group, as defined herein, where some or all of the hydrogens are replaced with halogen atoms. An exemplary haloalkyl group is trifluoromethyl.

The term "hydroxy" is an art term and as used herein refers to -OH.

The term "hydroxyalkyl" as used herein means that at least one hydroxy group, as defined herein, is attached to the parent molecular moiety through an alkyl group, as defined herein. present memory. Representative examples of hydroxyalkyl include, for example, hydroxymethyl, 2-hydroxyethyl,

3-hydroxypropyl, 2,3-dihydroxypentyl and 2-ethyl-4-hydroxyheptyl.

The term "silyl" as used herein includes hydrocarbyl derivatives of the silyl group (H3Si-) (ie, (hydrocarbyl) 3Si-), where the hydrocarbyl groups are univalent groups formed by elimination of a hydrogen atom of a hydrocarbon, e.g. eg, ethyl, phenyl. The hydrocarbyl groups can be combinations of different groups that can be varied to provide various silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2- (trimethylsilyl) ethoxy] methyl (SEM).

The term "silyloxy", as used herein, means that a silyl group, as defined herein, is attached to the parent molecule through an oxygen atom.

Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. Furthermore, the compounds of the present invention can also be optically active. The present invention contemplates that all of these compounds, including cis and trans isomers, (R) and (S) enantiomers, diastereoisomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, and other mixtures of they are within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All of these isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for example, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the enantiomers. desired pure. Alternatively, when the molecule contains a basic functional group, such as amino, or an acid functional group, such as carboxyl, diastereomeric salts are formed with a suitable optically active acid or base, followed by resolution of the diastereomers thus formed by crystallization. fractionated or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that "substitution" or "substituted with" includes the implicit condition that said substitution is according to the allowed valence of the substituted atom and the substituent, and that the substitution results in a stable compound, p. eg, a compound that does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, (cycloalkyl) alkoxy, hydroxy, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl , silyl, ether, alkylthio, sulfonyl, aminosulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, heterocyclylalkyl, aromatic or heteroaromatic moieties, aminoalkyl, haloalkyl, fluoroalkyl (such as trifluoromethyl), haloalkoxy, cyano, or other substituents described above. The permissible substituents can be one or more and can be the same or different for the appropriate organic compounds.

The term "protecting group", as used herein, means temporary substituents that protect a potentially reactive functional group from unwanted chemical transformations. Examples of such protecting groups include carboxylic acid esters, silyl ethers of alcohols and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed .; Wiley: New York, 1991).

A "saturated" or "fully saturated" compound means that the referenced chemical structure does not contain any carbon-carbon multiple bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl.

An "unsaturated" or "partially saturated" compound means that the referenced chemical structure may contain one or more carbon-carbon multiple bonds, but is not aromatic. For example, an unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl.

For the purposes of the invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, back cover.

Other chemical terms herein are used in accordance with conventional usage in the art, as exemplified in The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all of these tautomeric forms of the compounds being within the scope of the invention. Unless otherwise indicated, the structures depicted herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the present compounds, are within the scope of the invention. Both the R and S stereochemical isomers, as well as all mixtures thereof, are included within the scope of the invention.

The chemical structure of Examples that are a mixture of diastereoisomers or a single diastereoisomer, but with an unknown relative configuration is drawn and named without a defined stereochemical configuration.

Herein, compound structures that are depicted with a particular stereochemistry and identified as "racemic" (or "rac-") refer to an equimolar mixture of a pair of enantiomers as described in IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Golden Book"). Compiled by AD McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). The corrected XML version online: http://goldbook.iupac.org (2006-) created by M. Nic, J. Jirat, B. Kosata; updates compiled by A. Jenkins. ISBN 0-9678550-9-8. https://doi.org/10.1351/goldbook.

Examples 1-22, 24-37, 40-41, 48-67 are racemic mixtures (ie, not enantiomerically enriched). The structures (when drawn stereochemically) represent only a relative configuration. Thus, stereochemically drawn racemates are named with the prefix "rac-".

Examples 23, 38-39, 42-44, 46-47, 68-71 are enantiomerically enriched compounds, mainly with> 99% enantiomeric excess. The structures show an absolute configuration of the predominant enantiomer. Therefore, enantiomerically enriched compounds do not include the prefix "rac-" in their chemical names.

Example 25 is a mixture of two diastereoisomers. The configuration in the structure around the cyclohexane ring is relative and around the pinanediol moiety is an absolute configuration.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that, within the scope of good medical judgment, are suitable for use in contact with human tissues. and animals without excess toxicity, irritation, allergic response or other problems or complications, in proportion to a reasonable risk / benefit ratio.

The term "pharmaceutically acceptable salt" as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric. , pamoic (embonic), succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic and other acids. Pharmaceutically acceptable salt forms can include forms in which the ratio of molecules comprising the salt is not 1: 1. For example, the salt may comprise more than one molecule of organic or inorganic acid per molecule of base, such as two molecules of hydrochloric acid per molecule of compound of Formula (I). As another Example, the salt may comprise less than one molecule of organic or inorganic acid per molecule of base, such as two molecules of the compound of Formula (I) per molecule of tartaric acid.

As used herein, a protic solvent is a solvent that has a hydrogen atom attached to an oxygen (as in a hydroxyl group) or a nitrogen (as in an amine group). Generally speaking, any solvent that contains ^{labile H +} is called a protic solvent. The molecules of these solvents readily donate protons (H ⁺ ) to the reactants. In contrast, an aprotic solvent is a solvent that does not have a hydrogen atom attached to an oxygen (as in a hydroxyl group) or a nitrogen (as in an amine group), and cannot donate hydrogen.

As used herein, a polar protic solvent is a protic solvent that will dissolve many salts. In general, these solvents have high dielectric constants and high polarity. Non-limiting examples of polar protic solvents include acetic acid, ammonia, ethanol, formic acid, isopropanol, methanol, n- butanol, nitromethane, n-propanol, t-butanol, and water.

As used herein, a polar aprotic solvent is a solvent that will dissolve many salts, but lacks acidic hydrogen; these solvents generally have dielectric constants and intermediate to high polarity. Non-limiting examples of polar aprotic solvents include acetone, acetonitrile, dichloromethane (DCM), dimethyl sulfoxide (DMSO), ethyl acetate, hexamethylphosphoric triamide (HMPT), N, N-dimethylformamide (DMF), and tetrahydrofuran (THF).

As used herein, a nonpolar aprotic solvent is a solvent that will dissolve many salts, but lacks acidic hydrogen; these solvents generally have low dielectric constants and polarity. Non-limiting examples of nonpolar aprotic solvents include benzene, chloroform, cyclohexane, diethyl ether, hexane, pentane, and toluene.

A physician or veterinarian skilled in the art can easily determine and prescribe the therapeutically effective amount of the required pharmaceutical composition. For example, the physician or veterinarian may start the doses of the pharmaceutical composition or compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors influencing the effective amount may include, for example, the severity of the patient's condition, the disorder being treated, the stability of the compound, the mode of administration, the bioavailability of the particular compound, and, if desired, another type of therapeutic agent that is administered with the compound of the invention. A larger total dose can be administered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those of skill in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882.

That modulates "or" modulates "refers to the treatment, prevention, suppression, improvement or induction of a function, condition or disorder.

The term "treating" includes prophylactic and / or therapeutic treatments. The term "prophylactic or therapeutic" treatment is recognized in the art and includes administration to the host of one or more of the subject compositions. If administered prior to the clinical manifestation of the unwanted condition (eg disease or other unwanted condition of the host animal) then the treatment is prophylactic (i.e. protects the host against the development of the unwanted condition) , whereas if administered after the onset of the unwanted condition, the treatment is therapeutic (ie, aimed at diminishing, ameliorating, or stabilizing the existing unwanted condition or the side effects thereof).

As used herein, "subject" refers to a warm-blooded animal such as a mammal, preferably a human, or a human child, that is affected, or has the potential to be affected by, one or more diseases and disorders described herein.

"EC ⁵⁰ " refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response that is 50% of the maximum expression of a particular response that is induced, elicited, or potentiated by the compound. of particular test.

"IC ⁵⁰ " refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures that response.

Compounds of the invention

In general, the description provides a compound represented by Formula (I)

where:

L is -CO ² H, -C (O) O ((C ¹ -C ⁶ ) alkyl), -CO ² CH ² -O-pivaloyl, -CO ² CH ² OCO ² -isopropyl, -C (O) NHOH , -C (O) NHCN, -C (O) NH ² ,

-C (O) NH ((C ¹ -C ⁶ ) alkyl), -C (O) N ((C ¹ -C ⁶ ) ^{alkyl) 2} , -C (O) NH (aryl), -C (O) N (aryl) ((C ¹ -C ⁶ ) alkyl), -C (O) N (aryl) ² , -C (O) NH ((C ¹ -C ⁶ ) haloalkyl), -S (O) ² NH ² , -S (O) ² NH ((C ¹ -C ⁶ ) alkyl), -S (O) ² NH (haloalkyl (C ¹ -C ⁶ )), -S (O) ² NH (aryl), - S (O) ² NHC (O) ((C ¹ -C ⁶ ) alkyl), -S (O) ² NHC (O) (haloalkyl (C ¹ -C ⁶ )), -S (O) ² NHC (O ) (aryl), -N (H) S (O) ² ((C ¹ -C ⁶ ) alkyl), -N (H) S (O) ² (aryl), N (H) S (O) ² ( (C ¹ -C ⁶ ) haloalkyl), -NHC (O) ((C ¹ -C ⁶ ) alkyl), -NHC (O) ((C ¹ -C ⁶ ) haloalkyl), -NHC (O) (aryl) ,

-NHC (O) NH ((C ¹ -C ⁶ ) alkyl), -NHC (O) NH (aryl), -C (O) N (H) S (O) ² ((C ¹ -C ⁶ alkyl) ), -C (O) N (H) S (O) ² (aryl), -C (O) N (H) S (O) ² (halo (C ¹ -C ⁶ )), -P (O) (OH) ² , -CF ³ ,

R ¹ is selected from the group consisting of H, ^{straight or branched (C i} -C ⁶ ) alkyl, and (C ⁱ -C ⁶ ) alkyl -C (O) -;

X, Y, and Z are each independently selected from the group consisting of a bond, -C (R ') (R "') -, -C (R '") ² -, = CR "' -, -CHF -, -CF ² -, -NR '"-, = N-, -O-, -C (O) -, -S-, -S (O) - and -SO ² -, where

either of two ^{adjacent -CH 2} - groups optionally represent two members of a (C ³ -C ¹⁴ ) cycloalkenyl group or a (C ³ -C ¹⁴ ) heterocycloalkylenyl group,

no more than two of X, Y and Z simultaneously represent a bond; and no two adjacent members of X, Y and Z are simultaneously -O-, -S-, = N-, or -NR '"-;

X and Y or Y and Z optionally represent a fused aryl or heteroaryl ring having 3 to 7 atoms as ring members,

0 Z and L optionally form a fused lactone ring having 4 to 7 atoms as ring members including one or two O ring atoms;

m, n, p are independently integers between 0 and 2 inclusive, where at least one of m, n, p is not 0; eleven

l 'v' 1 optionally represents one or more double bonds;

R ² and R ³ are each independently selected from hydrogen, ^{straight or branched (C 1} -C ⁶ ) alkyl, or C (O) -R ', or R ² and R ³ taken together with the boron atom and the atoms of oxygen to which they are attached form a 4-, 5-, 6- or 7-membered ring that is fully or partially saturated,

or R ² and R ³ taken together with the boron atom and the oxygen atoms to which they are attached form a diester of boronic acid and pinanediol,

or R ² and R ³ taken together with the boron atom and the oxygen atoms to which they are attached form an anhydride of boronic acid and N-methyliminodiacetic acid;

V is selected from -C (R ') (R ") -, -NR'-, or -C (F) (R') -, -CHF-;

W is selected from -C (R ') (R "') -, -C (R">, -CHF-, -CF ² -, -NR '"-, or -C (O) -;

D is selected from alkylene (C ¹ -C ^s) alkyl, alkenylene- (C ² -C ⁸⁾ linear or branched alkynylene (C ² -C ⁸⁾ linear or branched, arylene (C ³ -C ^14), or cycloalkylene (C ³ -C ¹⁴ ),

wherein one or more -CH ² - groups in D are optionally and independently replaced with a residue selected from O, NR ', S, SO, SO ² or CR'R "; -CHF-, CF ² -, or

wherein either of two ^{adjacent -CH 2} -groups optionally represent two members of a cycloalkylenyl- (C ³ -C ¹⁴ ) group; Y

wherein no two ^{adjacent -CH 2} - groups are simultaneously replaced with O, NR ', S, SO, or SO ² ; R ', R "and R'" each independently H, OH, S (O) R ^d, S (O) ² R ^d, (C ¹ -C ^8), aryl (C ³ -C ⁶ are selected ), -NH ² ,

-NH (C ¹ -C ⁶ ) alkyl, -N [(C ¹ -C ⁶ ) ^{alkyl] 2} , -NR ^d SO ² N (R ^e ) ² , -NR ^d C (NR ^e ) N (R ^g ) ² , -C (O) NR ^d R ^e , -C (O) (C ¹ -C ⁶ ) alkyl, -C (O) aryl (C ³ -C ¹⁴ ), -C (O) O (C ¹ -C) alkyl ⁶ ), -C (O) Oaryl (C ³ -C ¹⁴ ), cycloalkyl (C ³ -C ⁶ ), heterocycloalkyl (C ³ -C ¹⁴ ), -C (O) heterocycloalkyl (C ³ -C ¹⁴ ), heteroaryl (C ³ -C ¹⁴ ), aryl (C ³ -C ¹⁴ ) -alkylene (C ¹ -C ⁶ ) -, -C (O) aryl (C ³ -C ¹⁴ ) -alkylene (C ¹ -C ⁶ ) - ,

-C (O) aryl (C ³ -C ¹⁴ ), cycloalkyl (C ³ -C ⁶ ) -alkylene (C ¹ -C ⁶ ) -, heteroaryl (C ³ -C ¹⁴ ) -alkylene (C ¹ -C ⁶ ) -, heterocyclyl (C ³ -C ¹⁴ ) -alkylene (C ¹ -C ⁶ ) -; and wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more selected from the group consisting of halogen, (C ¹ -C ³ ) alkyl, -COOH, -CN, -NO ² , -OH, -NR ^d R ^e , -NR ^g S (O) ² R ^h , (C ¹ -C ⁶ ) alkoxy, (C ³ -C ¹⁴ ) aryl, heterocyclyl having 3 to 7 atoms as ring members , halo (C ¹ -C ⁸ ) or aryloxy (C ³ -C ¹⁴ );

wherein R ^d, R ^e, R ^g, and R ^h each independently selected from H, alkyl ^(C1 - ^C6) alkyl, aryl (C ³ -C ¹⁴⁾ alkylene (C ¹ -C ⁶⁾ - optionally substituted, optionally substituted aryl (C ³ -C ¹⁴ ), hydroxyalkyl (C ¹ -C ⁶ ), aminoalkyl (C ¹ -C ⁶ ), H ² Nalkylene (C ¹ -C ⁶ ) -, cycloalkyl (C ³ - C ⁶⁾ optionally substituted heterocycloalkyl (C ³ -C ¹⁴⁾ , optionally substituted heteroaryl (C ³ -C ¹⁴⁾ , optionally substituted aryl (C ³ -C ¹⁴⁾ -alkylene (C ¹ -C ⁶⁾ - optionally substituted NR 'R "C (O) -, or aryl (C ³ -C ⁶ ) -cycloalkylene- (C ³ -C ¹⁴ ) -,

or R 'and R'"taken together represent -alkyl (C ⁱ -C ³ ) -N (Me) -alkyl (C ⁱ -C ³ ) -,

or a pharmaceutically acceptable tautomer, stereoisomer, racemate, salt, ester, solvate, polymorph, or prodrug thereof;

provided that the compound according to Formula (I) is not

1-amino-3- (4-boronobutyl) cyclobutane-1-carboxylic acid,

1-amino-3- (2-boronoethyl) cyclobutane-1-carboxylic acid,

1-amino-3- (boronomethyl) cyclobutane-1-carboxylic acid,

1-amino-3- (3-boronopropyl) cyclopentane-1-carboxylic acid, nor

1-amino-3- (3-boronopropyl) cyclohexane-1-carboxylic acid.

The general Formula (I) defined above encompasses certain compounds of the description, which can be described in more detail as follows.

In certain embodiments, L is CO ² H.

In certain embodiments, R ¹ is H or CH ³ .

In certain embodiments, R ² is H and R ³ is H.

In certain embodiments, X is -CH ² - or C (Me) ² .

In certain embodiments, Y is -CH ² - or C (Me) ² .

In certain embodiments, W is -CH ² -.

In certain embodiments, D is -CH ² -.

In certain embodiments, V is = CH- or -CH (Me) -.

In certain embodiments, Z is selected from CH (OH), C (Me) OH, CH (CH ² NH ² ), CH (CH ² NMe ² ), CH (CH ² NHMe), CH (CH ² CH ² NMe ² ), CH (CH ² -pyrrolidinyl), CH (CH ² -piperidinyl), or CH (CH ² CH ² -pyrrolidinyl).

In certain embodiments, p is 1, and n and m are 0 or 1.

In certain embodiments,

R ¹ is H; R ² is H; R ³ is H;

D is -CH ² -;

L is CO ² H, CO ² Et, CO ² CH ² -O-pivaloyl, or CO ² CH ² OCO ² -isopropyl;

V is C, CH, or CMe;

W is C, CH, CH ² , or CHMe;

X is CH, CH ² , CHOH, CHNH ² , CHCH ² NH ² , NBn, NH, CMe ² , CHCH ² NMe ² , CHCH ² -pyrrolidinyl, CHCH ² CH ² -pyrrolidinyl, CHCH ² -piperidinyl, or CHCH ² CH ² -piperidinyl;

Y is a bond or CH, CH ² , CHOH, CHNMe ² , CHCH ² NMe ² , CHCH ² CH ² NMe ² , CHCH ² -pyrrolidinyl, CHCH ² CH ² -pyrrolidinyl, CHNH ² , CMe ² , CHCH ² OH, CHCH ² -piperidinyl, or CHCH ² CH ² -piperidinyl;

Z is a bond or CH ² , CHOH, CHCH ² NMe ² , CHCH ² NH ² , CHCH ² -morpholinyl, CHCH ² NMeBn, CHCH ² -pyrrolidinyl, C (OH) Me, C (OH) -4-chlorobenzyl, CHCH ² -piperidinyl, CHCH ² CH ² -piperidinyl, C-CH ² -azetidinyl, CHCH ² -azetidinyl, CHCH ² CH ² -azetidinyl, CMeCH ² -azetidinyl, CHCH ² -azepanyl, CHCH ² - (4,4-dimethylpiperidinyl) , CHCH ² - (8-azabicyclo [3.2.1] octyl), CHCH ² - (2,2,6,6-tetramethylpiperidinyl), C (Me) CH ² -pyrrolidinyl, CHCH ² - (7-azabicyclo [2.2. 1] heptyl), CHCH ² -isoindolinyl, CHCH ² - (4,5-dichloroisoindolinyl), CHCH ² -tetrahydroisoquinolinyl, CHCH ² - (4-chlorophenyl-piperidinyl), CHCH ² -NHMe, CHCH ² -NHiPr, CHCH ² - NH- (4-chlorobenzyl), CHCH ² -N (Me) iPr, CHCH ² -NH-CH ² CF ³ , CHCH ² -NMe-CH ² CF ³ , CHCH ² -NHAc, CHCH ² -NHMs, CHCH ² - NH-SO ² NH ² , CHCH ² CH ² NH ² , CHCH ² -OH, CHCH ² -NH- (4-chlorophenyl), CHCHMe-pyrrolidinyl, CHNHMs, CHNHSO ² NH ² , CHCH ² SO ² NH ² , CHNH ² , CHNMe ² , CH-pyrrolidinyl, CHCH ² CH ² -pyrrolidinyl, or CHCH ² CH ² -piperidi Nile;

m is 1 or 2; n is 0 or 1; and p is 0 or 1.

In certain embodiments,

R ¹ is H; R ² is H; R ³ is H;

D is -CH ² -;

L is CO ² H, CO ² Et, CO ² CH ² -O-pivaloyl, or CO ² CH ² OCO ² -isopropyl;

V is CH or CMe;

W is CH ² or CHMe;

X is CH ² , CHOH, CHCH ² NH ² , NBn, NH, CMe ² , CHCH ² NMe ² , or CHCH ² -pyrrolidinyl;

Y is a bond or CH ² , CHOH, CHCH ² NMe ² , CHCH ² -pyrrolidinyl, CHNH ² , CMe ² , or CHCH ² OH;

Z is a bond or CH ² , CHOH, CHOMe, CHOAc, CHCH ² NMe ² , CHCH ² NH ² , CHCH ² -morpholinyl, CHCH ² NMeBn, CHCH ² -pyrrolidinyl, C (OH) Me, C (OH) -4 -chlorobenzyl, CHCH ² -piperidinyl, CHCH ² -azetidinyl, CHCH ² -azepanyl, CHCH ² - (4,4-dimethylpiperidinyl), CHCH ² - (8-azabicyclo [3.2.1] octyl), CHCH ² - (2, 2,6,6-tetramethylpiperidinyl), C (Me) CH ² -pyrrolidinyl, CHCH ² - (7-azabicyclo [2.2.1] heptyl), CHCH ² -isoindolinyl, CHCH ² - (4,5-dichloroisoindolinyl), CHCH ² -tetrahydroisoquinolinyl, CHCH ² - (4-chlorophenyl-piperidinyl), CHCH ² -NHMe, CHCH ² -NHiPr, CHCH ² -NH- (4-chlorobenzyl), CHCH ² -N (Me) iPr, CHCH ² -NH- CH ² CF ³ , CHCH ² -NMe-CH ² CF ³ , CHCH ² -NHAc, CHCH ² -NHMs, CHCH ² -NH-SO ² NH ² , CHCH ² CH ² NH ² , CHCH ² -OH, CHCH ² - NH- (4-chlorophenyl), CHCHMe-pyrrolidinyl, CHNHMs, CHNHSO ² NH ² , CHCH ² SO ² NH ² , CHNH ² , CHNMe ² , or

CH-pyrrolidinyl;

m is 1; n is 0 or 1; and p is 0 or 1.

In certain embodiments,

R ¹ is H; R ² is H; R ³ is H;

D is -CH ² -;

L is CO ² H;

V is CH or CMe;

W is CH ² or CHMe;

X is CH ² , CHOH, CHCH ² NH ² , NBn, or NH;

Y is CH ² ;

Z is a bond or CH ² , CHOH, CHOMe, CHCH ² NMe ² , CHCH ² NH ² , CHCH ² -morpholinyl, CHCH ² NMeBn, or CHCH ² -pyrrolidinyl;

m is 1; n is 1; and p is 0 or 1.

In the above definitions, Ac indicates acetyl, Bn indicates benzyl, Et indicates ethyl, iPr indicates isopropyl, and Ms indicates methanesulfonyl.

In certain embodiments, the compounds of Formula (I) according to the description have the structure of Formula (Ia):

where:

Z is -C (R ') (R "') -;

Y is bond, -C (R ') (R "') -, -NR"'- or -O-;

R 'and R'"are each independently hydrogen, -OH, (C ⁱ -C ⁸ ) alkyl, or -NH ² , where alkyl is optionally substituted with -NR ^d R ^e or heterocyclyl having 3 to 7 atoms as members of the ring;

wherein R ^d and R ^e are each independently hydrogen, ^{straight or branched (C 1} -C ⁶ ) alkyl, aryl (C ³ -C ¹⁴ ) alkylene (C ¹ -C ⁶ ) - optionally substituted, or aryl (C ³ - C ¹⁴ ) optionally substituted;

or a pharmaceutically acceptable tautomer, stereoisomer, racemate, salt, ester, solvate, polymorph, or prodrug thereof;

provided that the compound according to Formula (I) is not

1-amino-3- [3- (dihydroxyboranyl) propyl] cyclopentane-1-carboxylic acid, or

1-amino-3- [3- (dihydroxyboranyl) propyl] cyclohexane-1-carboxylic acid.

In certain embodiments, the compounds of Formula (I) according to the description have the structure of Formula (Ia) wherein

Z is -C (R ') (R "') -;

Y is a bond, -CH ² -, -NR "'- or -O-;

R 'and R'"are each independently hydrogen, -OH, (C ¹ -C ⁸ ) alkyl, or -NH ² , wherein alkyl is optionally substituted with -NR ^d R ^e or heterocyclyl having 3 to 7 atoms as members of the ring;

wherein R ^d and R ^e are each independently hydrogen, ^{straight or branched (C 1} -C ⁶ ) alkyl, aryl (C ³ -C ¹⁴ ) alkylene (C ¹ -C ⁶ ) - optionally substituted, or aryl (C ³ - C ¹⁴ ) optionally substituted;

or a pharmaceutically acceptable tautomer, stereoisomer, racemate, salt, ester, solvate, polymorph, or prodrug thereof;

provided that the compound according to Formula (I) is not

1-amino-3- [3- (dihydroxyboranyl) propyl] cyclohexane-1-carboxylic acid.

In one aspect, the invention provides a compound represented by Formula (Ib):

where:

R 'is -OH, (C ¹ -C ⁸ ) alkyl, or -NH ² , wherein alkyl is optionally substituted with -NR ^d R ^e or heterocyclyl having 3 to 7 atoms as ring members;

wherein R ^d and R ^e are each independently hydrogen, straight or branched ^{(C 1} -C ^{6) alkyl,}

aryl (C ³ -C ¹⁴ ) alkylene (C ¹ -C ⁶ ) - optionally substituted or aryl (C ³ -C ¹⁴ ) optionally substituted,

or a pharmaceutically acceptable tautomer, stereoisomer, racemate, salt, ester, solvate, or polymorph thereof. In certain embodiments, the compounds of Formula (Ib) according to the invention have the structure of Formula (Ib-1):

In certain embodiments, the compounds according to the invention have the structure of Formula (Ib) or Formula (Ib-1) wherein R 'is -CH ² NH ² , -CH ² NHCH ³ , -CH ² NHC (CH ³ ) ³ , -CH ² N (CH ³ ) ² , -CH ² N (CH ³ ) (CH ² CH ³ ), -CH ² N (CH ² CH ³ ) ² , -CH ² N (CH ³ ) (CH (CH ³ ) ² ), -CH ² -pyrrolidinyl, -CH ² -piperidinyl, -CH ² - (7-azabicide [2.2.1] heptyl), -CH ² -morpholinyl, -CH ² NCH ³ Bn,

-CH ² - (4,4-dimethylpiperidinyl), -CH ² -isoindolinyl, -CH ² - (4-c-chlorophenyl-piperidinyl), -CH ² -tetrahydroisoquinolinyl, -CH ² N (CH ³ ) Ph, -CH ² N (CH ³ ) (4-CH ³ OC ⁶ H ⁴ ) or -CH ² N (CH ³ ) (dichlorobenzyl).

In certain embodiments, the compounds according to the invention have the structure of Formula (Ib) or Formula (Ib-1) wherein

R 'is (C ¹ -C ⁴ ) alkyl substituted with -NR ^d R ^e or a heterocyclyl having 5 to 6 atoms as ring members; wherein R ^d and R ^e are each independently H or straight, branched ^{(C 1} -C ^{6) alkyl.}

In certain embodiments, the compounds according to the invention have the structure of Formula (Ic):

where

R ^d and R ^e are each independently selected from hydrogen, straight or branched ^{(C 1} -C ^{6) alkyl,}

or R ^d and R ^e combine with the nitrogen atom to which they are attached to form a heterocyclyl having 5 to 6 atoms as ring members

In certain embodiments, the compounds of Formula (Ic) according to the invention have the structure of Formula (Ic-1):

In certain embodiments, the compounds according to the invention have the structure of Formula (Ic) or Formula (Ic-1) wherein

-N (R ^d ) (R ^e ) is -NH ² , -NHCH ³ , -NHC (CH ³ ) ³ , -N (CH ³ ) ² , N (CH ³ ) (CH ² CH ³ ), N (CH ² CH ³ ) ² , N (CH ³ ) (CH (CH ³ ) ² ), -NCH ³ Bn, -N (CH ³ ) (4-CH ³ OC ⁶ H ⁴ ), -N (CH ³ ) (dichlorobenzyl ) or -N (CH ³ ) Ph,

or R ^d and R ^e combine with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, (7-azabicyclo [2.2.1] heptyl), morpholinyl, (4,4-dimethylpiperidinyl), isoindolinyl, ( 4-chlorophenyl-piperidinyl) or tetrahydroisoquinolinyl.

In certain embodiments, the compounds according to the invention have the structure of Formula (Ic) or Formula (Ic-1) wherein

-N (R ^d ) (R ^e ) is -NH ² , -NHCH ³ , -NHC (CH ³ ) ³ , -N (CH ³ ) ² , N (CH ³ ) (CH ² CH ³ ), N (CH ² CH ³ ) ² or N (CH ³ ) (CH (CH ³ ) ² ), or R ^d and R ^e combine with the nitrogen atom to which they are attached to form pyrrolidinyl, piperidinyl or (7-azabicyclo [2.2. 1] heptyl).

In certain embodiments, the compounds according to the invention are racemates:

1-amino-5- (2-boronoethyl) -2-hydroxycidohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2- (morpholinomethyl) cyclohexane-1-carboxylic acid;

1-amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid;

1-amino-2- (aminomethyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid;

2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolin-2 (7H) -yl) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - (((2,2,2-trifluoroethyl) amino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (dimethylamino) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid; or

1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid

or a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer, or a solvate thereof. In certain embodiments, the compounds according to the invention are:

rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid;

rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid;

rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2- (morpholinomethyl) cyclohexane-1-carboxylic acid;

1-amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡rrol¡d¡n-1-¡lmeth¡l) cyclohexane-1 acid -carboxylic;

(1R, 2S, 5R) -1-am¡no-5- (2-boronoeth¡l) -2- (p¡rrol¡d¡n-1-¡lmeth¡l) cyclohexane-1-carboxylic acid co;

1-amino-2- (amnomethyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2- (2- (p¡rrol¡d¡n-1-¡l) eth¡l) c¡dohexane-1-carboxylic acid co;

acid rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2 - ((4,4-d¡met¡lp¡per¡per¡n-1 -L) methyl) carboxylic cyclohexane;

acid rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-chlorophenyl) p¡per¡d¡n- 1-l) methyl) carboxylic cyclohexane; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzl) (methyl) am Not) methyl) carboxylic cyclohexane; acid rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (¡so¡ndol¡n-2-¡lmet¡l) cyclohexanecarboxyl¡ co;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((diethyl) methyl) cyclohexanecarboxylic acid ;

acid rac- (1R, 2S, 5R) -1-amno-5- (2-boronoet¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) cyclohexanecarboxylic co;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((sopropyl (methyl) amino) methyl) acid cyclohexanecarboxylic;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((tert-butylamine) methyl) cyclohexanecarboxylic acid ;

Rac- acid (1R, 2S, 5R) -2- (7-azabiclo [2.2.1] heptan-7-methyl) -1-amino-5- (2-boronoet L) carboxylic cyclohexane; acid rac- (1R, 2S, 5R) -1-amino-5- (2-boronoet¡l) -2 - ((3,4-d¡h¡dro¡soqu¡nol¡n-2 (1H) -l) methyl) carboxylic cyclohexane; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-trifluoroethyl) amino) acid methyl) cyclohexanecarboxylic;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino ) methyl) carboxylic cyclohexane; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethyl) methyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamine) methyl) cyclohexanecarboxylic acid;

acid rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) c Clohexanecarboxylic;

acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (1- (dimethyl) ethyl) cyclohexanecarboxylic ;

acid (5R) -1-amino-5- (2-boronoethyl) -2- (2- (p¡rrol¡d¡n-1-¡l) eth¡l) cyclohexanecarboxyl¡ co;

(5R) -1-amino-5- (2-boronoethyl) -2- (2- (dimethylamine) ethyl) cyclohexanecarboxylic acid;

1,2-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (hydroxymethyl) cytohexanecarboxylic acid;

1-amino-3- (2-boronoethyl) -5- (dimethylamine) cydohexane-1-carboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane acid -1-carboxylic;

acid (1R, 2S, 5R) -1-amino-5- (2-boronoet¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) cyclohexane-1 -carboxylic; or

acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡rrol¡d¡n-1-¡lmet¡l) cyclohexane-1 -carboxylic

or a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer, or a solvate thereof. In certain enhancements, the compounds of Formula (I) as described are the L-enantiomers in the amino acid moiety.

In other embodiments, the compounds of Formula (I) as described are the D enantomers in the amino acid moiety.

In general, the enantiomers L (in relation to L-arginine where B (OH) ² is replaced by the rest of guanine, mostly with configuration (R) absolute around the tertiary carbon of the amino acid) are more biologically active than the D enantiomers (mostly with absolute (S) configuration around tertiary carbon of amino acid).

The following structures are described in this memorandum:

either as a free acid or a free base, or as a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer or a solvate thereof.

In general, the compounds of the description are:

(2S, 3R) -1-amino-3- (2-boronoethyl) -2-methylcyclopentane-1-carboxylic acid;

(2R, 3S) -1-amino-3- (2-boronoethyl) -2-methylcyclopentane-1-carboxylic acid;

(1S, 3S, 4S) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid;

(1R, 3R, 4R) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid;

(1R, 3S, 4S) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid;

(1S, 3R, 4R) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid;

(1S, 3S, 4S) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid;

(1R, 3R, 4R) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid;

(1R, 3S, 4S) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid;

(1S, 3R, 4R) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid;

(1S, 3R) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid;

(1R, 3S) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid;

(1 R, 3R) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid;

(1S, 3S) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid;

(1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

(1S, 2S, 5S) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

(1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

(1 R, 2S, 5S) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

(1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid;

(1R, 2R, 5S) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid;

(2S, 5R) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid;

(2R, 5S) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) ddohexane-1-carboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((dimethylammo) methyl) ddohexane-1-carboxylic acid;

(1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) ddohexane-1-carboxylic acid;

(1S, 2S, 5S) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cidohexane-1-carboxylic acid;

(1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) ddohexane-1-carboxylic acid;

(1R, 2S, 5S) -1-amino-5- (2-boronoethyl) -2 - ((dimethylammo) methyl) ddohexane-1-carboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidm-1-ylmethyl) ddohexane-1-carboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2- (pyrrolidm-1-ylmethyl) ddohexane-1-carboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidm-1-yl) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidm-1-yl) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-dorofeml) piperidin-1-yl) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-dorofeml) piperidin-1-yl) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-didorobendl) (methyl) amino) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - (((3,4-didorobendl) (methyl) amino) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (isomdolin-2-ylmethyl) ddohexanecarboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2- (isomdolin-2-ylmethyl) ddohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((diethylammo) methyl) ddohexanecarboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((diethylammo) methyl) ddohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pipendm-1-ylmethyl) ddohexanecarboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2- (pipendm-1-ylmethyl) ddohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) ammo) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) ammo) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ('(tert-butylammo) methyl) ddohexanecarboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((tert-butylammo) methyl) ddohexanecarboxylic acid;

(1R, 2S, 5R) -2- (7-azabiddo [2.2.1] heptan-7-ylmethyl) -1-ammo-5- (2-boronoethyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -2- (7-azabiddo [2.2.1] heptan-7-ylmethyl) -1-ammo-5- (2-boronoethyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolm-2 (1H) -yl) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolm-2 (1H) -yl) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-tnfluoroethyl) ammo) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-tnfluoroethyl) ammo) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxypheml) (methyl) amino) methyl) ddohexanecarboxylic acid; (1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxypheml) (methyl) amino) methyl) ddohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methyl (feml) ammo) methyl) ddohexanecarboxylic acid;

(1S, 2R, 5S) -1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) ddohexanecarboxylic acid;

(3R, 5R) -1-amino-3- (amnomethyl) -5- (2-boronoethyl) ddohexanecarboxylic acid;

(3S, 5S) -1-amino-3- (amnomethyl) -5- (2-boronoethyl) dohexanecarboxylic acid;

(3R, 5R) -1-amino-3- (2-boronoethyl) -5 - ((dimethylamine) methyl) ddohexanecarboxylic acid;

(3S, 5S) -1-amino-3- (2-boronoethyl) -5 - ((dimethyl) methyl) cytohexanecarboxylic acid;

(3R, 5S) -3-amino-5- (2-boronoethyl) piperidin-3-carboxylic acid;

(3S, 5R) -3-amino-5- (2-boronoethyl) piperidin-3-carboxylic acid;

(3R, 5S) -3-amino-5- (2-boronoethyl) ppendin-3-carboxylic acid;

(3S, 5S) -3-amino-5- (2-boronoethyl) p¡per¡d¡n-3-carboxylic acid;

(3R, 5S) -3-amino-5- (2-boronoethyl) -1-methylperidine-3-carboxylic acid;

(3S, 5R) -3-amino-5- (2-boronoethyl) -1-methylperidine-3-carboxylic acid;

(3R, 5R) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid;

(3S, 5S) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid;

(3R, 5S) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid;

(3S, 5R) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid;

(1 R, 5R) -1-amino-5- (2-boronoethyl) -2- (dimethylamine) ddohexane-1-carboxylic acid; or

(1S, 5S) -1-amino-5- (2-boronoethyl) -2- (dimethylamine) cydohexane-1-carboxylic acid;

or a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer, and / or a solvate thereof. In certain embodiments, the disclosed compounds may be pharmaceutically acceptable salts. For example, representative hydrochloride salts of the compounds described can be:

or a stereoisomer, a tautomer, and / or a solvate thereof.

In a particular embodiment, the compound of the invention is:

Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride; Rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride; Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride; Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; 1-Amino-5- (2-boronoethyl) -2- (morpholinomethyl) cyclohexane-1-carboxylic acid dihydrochloride;

1-Amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride; 1-Amino-2- (aminomethyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid dihydrochloride;

1-Amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexane-1-carboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cidohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-trifluoroethyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylammo) methyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) cyclohexanecarboxylic acid dihydrochloride; (5R) -1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid;

(5R) -1-Amino-5- (2-boronoethyl) -2- (2-dimethylammo) ethyl) cyclohexanecarboxylic acid dihydrochloride; 1,2-Diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride;

1-Amino-5- (2-boronoethyl) -2- (hydroxymethyl) cyclohexanecarboxylic acid dihydrochloride;

Rac- (1R, 5R) -1-amino-5- (2-boronoethyl) -2- (dimethylamino) cyclohexane-1-carboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidm-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride; or (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride;

or a solvate thereof.

In a particular embodiment, the compound of the invention is:

1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid;

2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (2- (dimethylamino) ethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid;

1-amino-2- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid;

1,2-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid;

1-amino-5- (2-boronoethyl) -2-hydroxycidohexane-1-carboxylic acid;

1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cidohexane-1-carboxylic acid; or

1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid;

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof,

In a particular embodiment, the invention refers to a compound selected from:

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (Yferc-butylamino) methyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) cyclohexanecarboxylic acid;

(5R) -1-amino-5- (2-boronoethyl) -2- (2- (dimethylamino) ethyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid;

1-amino-2- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid;

1-amino-4- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclopentane-1-carboxylic acid;

(5R) -1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid;

1,2-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid;

Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

Rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; or 1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid

or a pharmaceutically acceptable salt, and / or a solvate thereof.

In a particular embodiment, the invention refers to a compound selected from:

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid dihydrochloride; (1R, 2S, 5R) -2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) cyclohexanecarboxylic acid dihydrochloride; (5R) -1-Amino-5- (2-boronoethyl) -2- (2-dimethylamino) ethyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride;

(1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid;

1-Amino-2- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid dihydrochloride;

1-amino-4- (2-boronoethyl) -2 - ((dimethylamino) methyl) cidopentane-1-carboxylic acid;

(5R) -1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid;

1,2-diamino-5- (2-boronoethyl) acidhexanecarboxylic acid dihydrochloride;

Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride;

Hydrochloride rac- (1S, 2R, 5R) -1-amino-5- (2-boronoetil) -2-hydroxycyclohexane-1-carboxylic acid;

Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride;

Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride;

Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride;

Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride;

Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; or

1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid or a solvate thereof.

Pharmaceutical compositions of the invention

In another aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof; and a pharmaceutically acceptable carrier. In general, pharmaceutical compositions comprise (i) a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable stereoisomer, tautomer, salt, solvate or prodrug thereof; and (ii) a pharmaceutically acceptable carrier, including, for example, bioavailability enhancers, penetration enhancers, biopolymers, PLGA-based nanoparticles, sugar-based nanoparticles, coating to avoid harmful effects of the stomach environment, and either by protecting the compound of the invention or a derivative thereof, or by releasing the biologically active material beyond the stomach environment, such as in the intestine.

The exact nature of the carrier, or, for example, excipient or diluent, will depend on the intended use of the composition and may be suitable or acceptable for veterinary use and / or suitable or acceptable for human use. The composition can optionally include one or more additional compounds, including one or more additional therapeutic agents.

The compounds of the invention can be combined with other therapeutic agents. The compound of the invention and another therapeutic agent can be administered simultaneously or sequentially. When the other therapeutic agents are administered simultaneously, they can be administered in the same formulation or in separate formulations, but are administered at substantially the same time. The other therapeutic agents are administered sequentially with each other and with the compound of the invention, when the administration of the other therapeutic agents and the compound of the invention is temporarily separated. The time gap between the administration of these compounds may be a matter of minutes or it may be longer.

Examples of other therapeutic agents that can be administered with the compounds of the invention include steroids, membrane stabilizers, 5LO inhibitors, inhibitors of leukotriene and receptor synthesis, inhibitors of IgE isotype switching or IgE synthesis, isotype switching IgG or IgG synthesis, p-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, rituxan, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors and antihistamines, immunotherapeutic agents, including point inhibitors control agents such as PD-1, PD-L1, or CTLA-4 inhibitors and IDO / TDO inhibitors, immunosuppressants, agents that affect interleukins, cytokines, and chemokines, kinase inhibitors, chemotherapeutic agents including alkylating antineoplastic agents, antimetabolites , antimicrotubule agents, topoisomerase inhibitors, cytotoxic antibiotics or targeted therapies such as antibodies, antibody-drug conjugates, cell-based immunotherapies, nanoparticles, cancer vaccines, and radiation therapy.

In some embodiments, the one or more additional chemotherapeutic agents include aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothezomib, capetinoin. , carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyiviridine, dexamethasone, dienestrol, dichloroacetate Diethylstilbestrol, docetaxel, doxorubicin, epirubicin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, hydroxyurein, iodine, genisteinibrin, hydroxycitabine, genistein, iodine, gamma-urin, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Levamisole, Lomustine, Lonidamine, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Mesna, Metformin, Methotrexate, Miltefosine, Mitomycin, Mitotane, Mitoxanthrone, Octreotide Mk oxaliplatin, paclitaxel, pamidronate, pazopanib, pentostatin, periphosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, rucaparib, selumetinib, sorafenib, streptozocin, sunitinib, suramine, themozolidomide, tamidimolifen, suramine, talaidomolifenox, suramine, talaidomolide, talaidomidoxin, suramine, talaidomolifen, suramine, talaidomolide, talaidomide thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, or vinorelbine.

In some embodiments, the one or more additional chemotherapeutic agents include abagovomab, adecatumumab, afutuzumab, anatumomab mafenatox, apolizumab, blinatumomab, catumaxomab, durvalumab, epratuzumab, inotuzumab ozogamicin, intelumumab, ipizilumabumabumab, intelumumab, lambizolubumabumabumabumabrolizumabumab, pidilizumab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, the one or more additional immunotherapeutic agents include epacadostat, GDC-0919, 1-methyl-D-tryptophan, BMS-986205, or PF-06840003.

In some embodiments, the one or more additional chemotherapeutic agents include ipilimumab, nivolumab, pembrolizumab, or pidilizumab.

In other embodiments, the method further comprises administering one or more non-chemical methods of cancer treatment, such as radiation therapy, surgery, thermoablation, focused ultrasound therapy, cryotherapy, or a combination thereof.

As indicated above, an "effective amount" refers to any amount that is sufficient to achieve a desired biological effect. In combination with the teachings provided herein, choosing from among the various active compounds and weighting factors such as potency, relative bioavailability, patient's body weight, severity of adverse side effects, and preferred mode of administration, An effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial unwanted toxicity and yet is effective in treating the particular subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One skilled in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without the need for undue experimentation. Generally, it is preferred that a maximum dose be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day can be contemplated to achieve appropriate systemic levels of the compounds. Appropriate systemic levels can be determined by, for example, measuring the patient's maximum or sustained plasma level of the drug. The terms "dose" and "dosage" are used interchangeably herein.

Generally, daily oral doses of the active compounds will be, for human subjects, about

0.0001 milligrams / kg per day, 0.001 milligrams / kg per day, or 0.01 milligrams / kg per day to about 100 milligrams / kg per day or 1,000 milligrams / kg per day. Oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, are expected to yield the desired results. Dosage can be appropriately adjusted to achieve desired drug levels sufficient to achieve or maintain a desired local or systemic therapeutic effect, depending on the mode of administration. For example, intravenous administration is expected to be on the order of several orders of magnitude lower doses per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or higher effective doses by a different, more localized route of administration) may be employed to the extent permitted by the tolerance of the patient. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compounds. The compounds can be administered once a week, several times a week (eg, every other day), once a day, or multiple times a day, depending, among other things, on the mode of administration, the specific indication being treated. and the judgment of the prescribing physician.

In one embodiment, intravenous administration of a compound of the invention will typically be 0.1 mg / kg / day at

20 mg / kg / day.

Determination of an effective dosage of a compound for a particular use and mode of administration is within the capabilities of those skilled in the art. Effective dosages can be estimated initially from in vitro metabolism and activity assays. For example, an initial dosage of compound for use in animals can be formulated to achieve a circulating blood or serum concentration of the metabolite active compound that is at or above an IC50 of the particular compound as measured in as in vitro assay. Calculation of dosages to achieve said circulating blood or serum concentrations taking into account the bioavailability of the particular compound via the desired route of administration is within the limits of capabilities of those skilled in the art. Initial compound dosages can also be estimated from in vivo data, such as animal models. For any compound described herein, the therapeutically effective amount can be determined initially from animal models. A therapeutically effective dose can also be determined from human data for compounds of the invention that have been tested in humans and for compounds known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the potency and relative bioavailability of the administered compound. Adjusting the dose for maximum efficacy based on the methods described above and other methods that are well known in the art is well within the capabilities of one of ordinary skill in the art.

The formulations of the invention can be administered in pharmaceutically acceptable solutions, which can usually contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

Pharmaceutical compositions comprising the compound of the invention can be manufactured by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, retaining, or lyophilizing processes. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliaries, which facilitate processing of the compounds into pharmaceutically usable preparations.

For use in therapy, an effective amount of the compound of the invention can be administered to a subject by any mode that delivers the compound of the invention to the desired surface. Administration of the pharmaceutical composition of the present invention can be achieved by any means known to the person skilled in the art. Routes of administration include, for example, oral, buccal, nasal, rectal, vaginal, ocular, topical, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, direct injection (eg, into an abscess), mucosal, by inhalation and insufflation. .

For oral administration, the compounds (ie, the compounds of the invention and other therapeutic agents) can be readily formulated by combining the active compound (s) with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the invention to be formulated, for example, as tablets, pills, lozenges, lozenges, capsules, liquids, gels, syrups, solid suspensions, suspensions, for oral ingestion by a subject leaving to treat. Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after the addition of suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, binding agents, fillers, lubricants, disintegrants and wetting agents. Suitable fillers include sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Optionally, oral formulations can also be formulated in saline or buffers, e.g. eg, EDTA to neutralize internal acidic conditions or can be administered without any vehicle.

Oral dosage forms of the above component (s) are also specifically contemplated. The component (s) can be chemically modified so that oral administration of the derivative is effective. Generally, the chemical modification contemplated is the binding of at least one residue to the component molecule itself, where said residue allows (a) inhibition of acid hydrolysis; and (b) uptake into the bloodstream from the stomach or intestine. Increased overall stability of the component (s) and increased circulation time in the body are also desirable. Examples of such moieties include: polyethylene glycol, ethylene glycol and propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, p. 367-383 (1981); Newmark et al., J Appl Biochem 4: 185-9 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-thioxocane. Polyethylene glycol moieties are preferred for pharmaceutical use, as noted above.

For the component (or derivative), the site of release can be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. One skilled in the art has formulations available that will not dissolve in the stomach, but will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protecting the compound of the invention or by releasing the biologically active material beyond the stomach environment, such as in the intestine.

To ensure complete gastric resistance, a coating impermeable to at least pH 5.0 is essential. Examples of the most common inert ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, acetate phthalate Polyvinyl (PVAP), Eudragit L30D, Aquateric, Cellulose Acetate Phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings can be used as mixed films.

A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. These may include sugar coatings or coatings that make the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) for administration of dry therapeutic agent (eg, powder); for liquid forms, a soft gelatin shell can be used. The cover material for the stamps can be thick starch or other edible paper. For pills, lozenges, molded tablets, or crushed tablets, wet dough techniques can be used.

The therapeutic agent can be included in the formulation as multiparticulate fines in the form of granules or pellets of particle size of about 1 mm. The formulation of the material for the administration of capsules could also be as a powder, lightly compressed caps or even as tablets. The therapeutic agent could be prepared by compression.

Both colorants and flavorings can be included. For example, the compound of the invention can be formulated (such as by encapsulation in liposomes or microspheres) and then further contained within an edible product, such as a chilled beverage containing colorants and flavoring agents.

The therapeutic agent can be diluted or increased in volume with an inert material. These diluents could include carbohydrates, especially mannitol, □ -lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts can also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

Disintegrators can be included in the formulation of the therapeutic agent in a solid dosage form. Materials used as disintegrants include, for example, starch, including the commercial starch-based disintegrant, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethyl cellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite can be used. Another form of disintegrants are insoluble cation exchange resins. Powdered gums can be used as disintegrants and as binders and these can include powdered gums such as agar, karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

Binders can be used to hold the therapeutic agent together to form a hard tablet and include natural product materials such as acacia, tragacanth, starch, and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC), and carboxymethyl cellulose (CMC). Both polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could be used in alcoholic solutions to granulate the therapeutic agent.

An antifriction agent can be included in the formulation of the therapeutic agent to prevent sticking during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the die wall, and these can include, for example; stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000 can also be used.

Glidants could be added which could improve the flow properties of the drug during formulation and aid reorganization during compression. Glidants can include starch, talc, fumed silica, and hydrated silicoaluminate.

To aid dissolution of the therapeutic agent in the aqueous environment, a surfactant can be added as a wetting agent. Surfactants can include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents can be used and can include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene 10, 50 and 60 hydrogenated castor oil, glycerol monostearate, polysorbate 40, 60, 65 and 80, acid ester fatty sucrose, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention either alone or as a mixture in different ratios.

Pharmaceutical preparations that can be used orally include snap-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The snap-fit capsules can contain the active ingredients mixed with a filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. Such microspheres have been well defined in the art. All formulations for oral administration must be in dosages suitable for said administration.

Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils) and preservatives (eg, methyl or propyl phhydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavorings, colorants, and sweetening agents, as appropriate.

The pharmaceutical compositions, if desired, may be presented in a container or dispensing device, which may contain one or more unit dosage forms containing the compound (s). The package may comprise, for example, a metal or plastic foil, such as a blister package. The container or dispensing device may be accompanied by instructions for administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.

For topical administration, the compound can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, e.g. eg, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

For administration by inhalation, the compounds for use according to the present invention may conveniently be administered in the form of an aerosol spray presentation from pressurized containers or a nebulizer, with the use of a suitable propellant, e.g. eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, eg, gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

Pulmonary administration of the compounds of the invention is also contemplated herein. The compound of the invention is administered to the lungs of a mammal while inhaling and passes through the epithelial lining of the lung into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7: 565-569 (1990); Adjei et al., Int J Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13 (Suppl 5): 143-146 (1989) (Endothelin-1); Hubbard et al., Annal Int Med 3: 206-212 (1989) (^ 1-antitrypsin); Smith et al., 1989, J Clin Invest 84: 1145-1146 (α-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140: 3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., Pat. US No. 5,284,656 (Granulocyte Colony Stimulating Factor). A method and composition for pulmonary administration of drugs with systemic effect are described in US Pat. No. 5,451,569, issued September 19, 1995 to Wong et al.

A wide range of mechanical devices designed for pulmonary delivery of therapeutic products are contemplated for use in the practice of this invention including, for example, nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those of skill. in technique.

Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo .; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo .; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

All of these devices require the use of suitable formulations to dispense the compound of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants, and / or carriers useful in therapy. In addition, the use of liposomes, microcapsules or microspheres, inclusion complexes or other types of vehicles is contemplated. The chemically modified compound of the invention can also be prepared in different formulations depending on the type of chemical modification or the type of device used.

Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise the compound of the invention dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation can also include a buffer and a simple sugar (eg, for stabilization of the compound of the invention and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface-induced aggregation of the compound of the invention caused by atomization of the solution when forming the aerosol.

Formulations for use with a metered dose inhaler device will generally comprise a finely divided powder containing the compound of the invention suspended in a propellant with the aid of a surfactant. The propellant can be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid can also be useful as a surfactant.

Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing the compound of the invention and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts that facilitate dispersion of the powder from the device, p. eg, 50 to 90% by weight of the formulation. The compound of the invention should advantageously be prepared in the form of particles with an average particle size of less than 10 microns (pm), most preferably 0.5 to 5 pm, for most effective administration to distal areas of the lung.

Nasal administration of a pharmaceutical composition of the present invention is also contemplated. Nasal administration allows the passage of a pharmaceutical composition of the present invention into the bloodstream directly after administering the therapeutic product to the nose, without the need to deposit the product in the lung. Formulations for nasal administration include those with dextran or cyclodextran.

For nasal administration, a useful device is a small, hard bottle to which a metered-dose sprayer is attached. In one embodiment, the metered dose is administered by introducing the pharmaceutical composition of the solution of the present invention into a chamber of defined volume, the chamber having an opening sized for aerosolization and the aerosol formulation forming a spray when a liquid is compressed into the chamber. . The chamber is compressed to deliver the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

Alternatively, a squeeze plastic bottle with an opening or aperture sized is used to aerosolize an aerosol formulation into a spray when squeezed. The opening is typically at the top of the bottle, and the top is generally tapered to partially fit the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for delivery of a metered dose of the drug.

The compounds, when it is desirable to administer them systemically, can be formulated for parenteral administration by injection, e.g. eg, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage forms, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

Alternatively, the active compounds may be in powder form to be constituted with a suitable vehicle, eg, sterile, pyrogen-free water, buffer, dextrose solution, before use. To this end, the active compound can be dried by any technique known in the art, such as lyophilization, and reconstituted prior to use.

The compounds can also be formulated into rectal or vaginal compositions such as suppositories or retention enemas, e.g. g., containing conventional suppository bases such as cocoa butter or other glycerides.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

For ocular administration, the compound (s) can be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art.

In addition to the formulations described above, for prolonged administration, the compounds can also be formulated as a depot preparation for administration, for example, by implantation or injection. intramuscular. Such long-acting formulations can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as derivatives of limited solubility, for example, as a salt of limited solubility. . Alternatively, transdermal delivery systems manufactured as an adhesive patch or disc are used that slowly releases the compound for percutaneous absorption. For this purpose, permeation enhancers can be used to facilitate transdermal penetration of the compound.

The pharmaceutical compositions may also comprise suitable solid phase or gel carriers or excipients. Examples of such carriers or excipients include, for example, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encoded, coated on microscopic gold particles, contained in liposomes, nebulized, aerosols, granules for implantation in the skin or dried on a sharp object to be scratched on the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with prolonged release of active compounds, in the preparation of which excipients and additives are commonly used and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavors, sweeteners or solubilizers as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249: 1527-1533 (1990).

The compounds of the invention and optionally other therapeutic agents can be administered per se (without solvent) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salts must be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts thereof. Such salts include, for example, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic, malonic, succinic, naphthalene- 2-sulfonic, and benzenesulfonic. Furthermore, said salts can be prepared as alkali or alkaline earth metal salts, such as sodium, potassium or calcium salts of the carboxylic acid group. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having less solubility than the corresponding free acids and bases can also be formed.

The compounds can alternatively be formulated in the pharmaceutical composition per se, or in the form of a solvate.

Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (at 0.01-0.25% w / v) and thimerosal (at 0.004-0.02% w / v).

The pharmaceutical compositions of the invention contain an effective amount of a compound of the invention and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating substances that are suitable for administration to a human or other vertebrate animal. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate application. The components of the pharmaceutical compositions can also be mixed with the compounds of the present invention, and with each other, such that there is no interaction that substantially impairs the desired pharmaceutical efficacy.

The therapeutic agent (s), specifically including the compound of the invention, may be provided in particles. Particles, as used herein, mean nanoparticles or microparticles (or in some cases larger particles) that may consist of all or part of the compound of the invention or another therapeutic agent or agents as described in the present memory. The particles may contain the therapeutic agent (s) in a core surrounded by a coating, including, for example, an enteric coating. The therapeutic agent (s) can also be dispersed throughout the particles. The therapeutic agent (s) can also be adsorbed onto the particles. The particles can have release kinetics of any order, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent (s), any of the materials routinely used in the art of pharmacy and medicine including, for example, erodible, non-erodible, biodegradable or non-biodegradable material or combinations thereof. The particles can be microcapsules containing the compound of the invention in a solution or in a semi-solid state. The particles can be practically any shape.

Both biodegradable and non-biodegradable polymeric materials can be used in the manufacture of particles to deliver the therapeutic agent (s). Said polymers can be natural or synthetic polymers. The Polymer is selected on the basis of the period of time during which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26: 581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly (methyl methacrylates), poly (ethyl methacrylates), poly (butyl methacrylate), poly (isobutyl methacrylate), poly ( Hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), and poly (acrylate) octadecyl).

The therapeutic agent (s) may be contained in controlled release systems. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including, for example, sustained release and delayed release formulations. The term "sustained release" (also referred to as "prolonged release") is used in its conventional sense to refer to drug formulation that provides gradual release of a drug over an extended period of time, and which may, although not necessarily , preferably result in substantially constant blood levels of a drug over a prolonged period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and release of the drug therefrom. The "delayed release" may or may not involve the gradual release of the drug over a prolonged period of time and thus may or may not be a "sustained release".

The use of a long-term sustained release implant may be particularly suitable for the treatment of chronic conditions. "Long term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well known to those skilled in the art and include some of the delivery systems described above.

One skilled in the art in the relevant techniques will understand that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in light of the information known to one skilled in the art, and can be performed without departing from the scope of the invention or any embodiment thereof.

Uses of the invention

In one aspect, the invention provides a compound or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use in treating or preventing a disease or condition selected from the group consisting of cardiovascular disorders, sexual disorders, disorders wound healing, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, lung disorders, hemolytic disorders and cancers. In certain embodiments, the disease or condition is selected from the group consisting of cardiovascular disorders, sexual disorders, wound healing disorders, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, lung disorders, hemolytic disorders, and cancers.

In certain embodiments, the disease or condition is pulmonary hypertension (PAH).

In certain embodiments, the disease or condition is a lung disorder selected from the group consisting of chemically induced pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.

In certain embodiments, the disease or condition is an autoimmune disorder selected from the group consisting of encephalomyelitis, multiple sclerosis, antiphospholipid syndrome 1, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyradiculoneuropathy, dermatitis herpetiformis, dermatomyositis, myasthenia gravis, pemphigus, rheumatoid arthritis syndrome. stiff person, type 1 diabetes, ankylosing spondylitis, paroxysmal nocturnal hemoglobinuria (PNH), paroxysmal cold hemoglobinuria, severe idiopathic autoimmune hemolytic anemia, and Goodpasture syndrome.

In certain embodiments, the disease or condition is an immune disorder selected from the group consisting of myeloid-derived suppressor cell (MDSC) mediated T-cell dysfunction, human immunodeficiency virus (HIV), autoimmune encephalomyelitis, and ABO mismatch transfusion reaction. .

In certain embodiments, the disease or condition is a myeloid derived suppressor cell (MDSC) mediated T-cell dysfunction.

In certain embodiments, the disease or condition is a hemolytic disorder selected from the group consisting of sickle cell anemia, thalassemias, hereditary spherocytosis, stomatocytosis, microangiopathic hemolytic anemias, pyruvate kinase deficiency, infection-induced anemia, cardiopulmonary bypass, and anemia induced by mechanical heart valves and chemical-induced anemia.

In certain embodiments, the disease or condition is sickle cell anemia.

In certain embodiments, the disease or condition is a gastrointestinal disorder selected from the group consisting of gastrointestinal motility disorders, gastric cancers, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and gastric ulcers.

In certain embodiments, the disease or condition is a sexual disorder selected from the group consisting of Peyronie's disease and erectile dysfunction.

In certain embodiments, the disease or condition is an ischemic reperfusion injury (IR) selected from the group consisting of hepatic IR, renal IR, and myocardial IR.

In certain embodiments, the cancer is selected from the group consisting of gastric cancer, cancer of the gastroesophageal junction, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, non-small cell lung carcinoma, renal cell carcinoma, prostate carcinoma, multiple myeloma, acute and chronic leukemias, T-cell, B-cell, and NK-cell lymphomas, neuroblastoma, glioblastoma, astrocytoma, head and neck squamous cell carcinomas, and melanoma.

In certain embodiments, the disease or condition is selected from the group consisting of kidney disease inflammation, psoriasis, leishmaniasis, neurodegenerative diseases, wound healing, human immunodeficiency virus (HIV), hepatitis B virus (HBV), infections by Helicobacter pylori, fibrotic disorders, arthritis, candidiasis, periodontal disease, keloids, adenotonsillar disease, African sleeping disease and Chagas disease.

In certain embodiments, the disease or condition is selected from the group consisting of kidney disease inflammation, psoriasis, leishmaniasis, neurodegenerative diseases, wound healing, human immunodeficiency virus (HIV) infection, human immunodeficiency virus (HIV) infection. hepatitis B (HBV), hepatitis C virus (HCV) infection, Helicobacter pylori infections, fibrotic disorders, arthritis, candidiasis, periodontal disease, keloids, adenotonsillar disease, African sleeping sickness, and Chagas disease.

In certain embodiments, the disease or condition is a wound healing disorder selected from the group consisting of infected and uninfected wound healing.

In certain embodiments, the subject is a mammal selected from the group consisting of human, dog, cat, horse, cow, pig, sheep, goat, ape, and rodent.

In certain embodiments, the subject is a mammal selected from the group consisting of a mammal selected from the group consisting of human, dog, cat, horse, cow, pig, sheep, goat, and ape.

In certain embodiments, the method of treatment further comprises administering to the patient a therapeutically effective amount of an antiviral agent, a chemotherapeutic agent (including alkylating antineoplastic agents, antimetabolites, antimicrotubule agents), an immunosuppressant, radiation, an antitumor vaccine, an antiviral vaccine. , cytokine therapy and / or a tyrosine kinase inhibitor, an immunotherapeutic agent, including a checkpoint inhibitor such as PD-1, PD-L1 or CTLA-4 inhibitor and IDO / TDO inhibitor, immunosuppressant, agent affecting interleukins, cytokines, and chemokines, topoisomerase inhibitor, cytotoxic antibiotic, or targeted therapy such as antibody, antibody-drug conjugate, cell-based immunotherapy, nanoparticles, cancer vaccine, and radiation therapy before, simultaneously with, or after administration of the at least one compound according to the invention, or a stereoisomer, tautomer, sa l, solvate or pharmaceutically acceptable prodrug thereof.

In certain embodiments, the method of treatment further comprises administering to the subject a therapeutically effective amount of an antiviral agent, a chemotherapeutic agent including alkylating antineoplastic agents, antimetabolites, antimicrotubule agents (including, for example, oxaliplatin, gemcitabine, dacarbazine, temozolomide, doxorubicin , 5-fluorouracil), an immunosuppressant (including, for example, everolimus), immunomodulators (including, for example, checkpoint inhibitors: anti-PD-1, anti-PD-L1, anti-CTLA-4 and inhibitors of IDO / TDO), radiation, photodynamic therapy, tumor vaccines, oncolytic viruses, antiviral vaccines, cytokine and chemokine therapy or a tyrosine kinase inhibitor, agents that affect interleukins, topoisomerase inhibitors, cytotoxic antibiotics, targeted therapies such as antibodies, antibody-drug conjugates, cell-based immunotherapies, nanoparticles the, before, simultaneously with or after the administration of the at least one compound according to the invention, or a pharmaceutically acceptable stereoisomer, tautomer, salt, solvate or prodrug thereof.

In certain embodiments, the method of treatment further comprises administering to the subject a therapeutically effective amount of antibodies to PD-1, PD-L-1, or CTLA4.

In some embodiments, the cancer is chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cancer of the bile duct, cancer. bladder, bone cancer, brain tumor, brain and spinal cord tumor, brainstem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumors of the central nervous system, breast cancer, bronchial tumors, burkitt's lymphoma, carcinoid tumor, carcinoma of unknown primary, central nervous system cancer, cervical cancer, childhood cancers, chordoma, chronic myeloproliferative disorders, colon cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing's sarcoma, extracranial germ cell tumor, extrahepatic bile duct cancer, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors, tumor germ cell tumor, extracranial germ cell tumor, extragonadal germ cell, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular cancer, histiocytosis, langerhans cell cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, kaposi's sarcoma, kidney cancer, langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ, lymphoma, AIDS-related lymphoma, macroglobulinemia, cancer breast cancer, medulloblastoma, medulloepithelioma, merkel cell carcinoma, malignant mesothelioma, occult primary metastatic squamous neck cancer, midline tract carcinoma involving the nut gene, mouth cancer, multiple endocrine neoplasia syndrome, neoplasm plasma cell, mycosis fungoides, myeloma, chronic myeloproliferative disorder, cancer of the nasal cavity, cancer of the s paranasal ene, nasopharyngeal cancer, non-Hodgkin's lymphoma, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, papillomatosis, paraganglioma, paranasal sinus cancer, nasal cavity cancer, parathyroid, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors of intermediate differentiation, pineoblastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, primary central nervous system lymphoma, rectal cancer, real cell cancer, cancer of renal pelvis, ureter cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, sezary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, stomach cancer, primitive supratentorial neuroectodermal tumors itives, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, gestational trophoblastic tumor, unknown primary, unusual childhood cancer, urethral cancer, uterine cancer, sarcoma uterine, waldenstrom's macroglobulinemia, or wilms tumor.

Examples

The present invention is further illustrated by the following Examples. Comparative Examples are not within the scope of the invention.

Preparation and characterization methods

The compounds of the present disclosure can be prepared using known chemical reactions and procedures. Representative methods for synthesizing compounds of the disclosure are presented below. It is understood that the nature of the substituents required for the desired target compound often determines the method of synthesis. All variable groups of these methods are as described in the generic description if not specifically defined below.

Those skilled in the art will recognize that starting materials and reaction conditions can be varied, the sequence of reactions altered, and additional steps employed to produce compounds encompassed by the present disclosure, as demonstrated by the following Examples. Many general references are available that provide commonly known synthetic chemical schemes and conditions useful for synthesizing the disclosed compounds (see, e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley- Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

For more specific guidance on the synthetic strategy of boron-containing alpha-amino acids, the reader is referred to international patent application publications WO 11/133653 and WO 13/059437.

The reactions are carried out in an appropriate solvent for the reagents and materials used and suitable for the transformations that are being carried out. Those skilled in the art of organic synthesis will understand that the functionality present in the molecule must be consistent with the proposed transformations. This will sometimes require criteria to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the disclosure.

In some cases, the protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, the need for such protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis. An authoritative account describing the many alternatives to the trained professional is JFW McOmie, "Protective Groups in Organic Chemistry ', Plenum Press, London and New York 1973, in TW Greene and PGM Wuts, " Protective Groups in Organic Synthesis ", Third Edition, Wiley, New York 1999, in "The Peptides", Volume 3 (editors: E.

Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, vol. 1/15, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982, and / or in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974. The Protecting groups can be removed at a convenient later stage using methods known in the art.

Starting materials can be obtained from commercial sources or prepared by well-established literature methods known to those of skill in the art.

All solvents, substrates, and reagents that were commercially available were used without further purification. TLC analysis was performed using pre-coated glass plates (0.2 ± 0.03 mm thick, GF-254, particle size 0.01-0.04 mm) from Fluorochem Ltd, UK. Column chromatography was performed using high purity grade silica gel (60 A pore size, 220-440 mesh particle size, 35-75 µm particle size) from Fluka, Merck or Fluorochem.

Preparative HPLC was performed on Shimadzu LC-20AP with ELSD-LTII detector equipped with a 21.2 / 250 mm C18 Hypersil GOLD column, 5 µm.

The 1H and 13C NMR spectra were recorded on a Bruker AVANCE II PLUS NMR spectrometer (Ultra Shield) at

700 MHz.

19F NMR spectra were recorded on an AVANCE Bruker 200 MHz NMR spectrometer.

All spectra were recorded in appropriate deuterated solvents (CDCb, DMSO-d6, D2O, CD3OD, etc.) that were commercially available.

Resonances are given in parts per million relative to tetramethylsilane. The data are indicated as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad singlet), coupling constants in (Hz) and integration.

Specific rotations were measured on the polAAr 3001 Index Instruments polarimeter at 589 nm and 24 ° C.

ESI-MS spectra were obtained on a Shimadzu LC-20AD LPG separation module with an SPD-M20A UV detector and LCMS-2020 mass detector equipped with a 2.1 / 50 mm, 2, Kinetex C18 column. 6 µm eluted with 0.5 mL / min flow from a 10-90% gradient (over 6 min) of acetonitrile in water.

Exemplary general synthetic methodologies for preparing compounds of Formula (I) are provided below.

Exemplary general synthetic methodologies for preparing specific compounds of Formula (I) in an enantioselective manner are provided below.

,. . rt eriantiómef o (f? l can be found two separable epmoros> 99% «

An alternative enantioselective method is provided below.

Synthesis of intermediates:

Intermediate 1. ethyl rac- (1R, 2R, 4R) -2-Acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate.

Step A. Ethyl 2-Oxocyclohex-3-ene-1-carboxylate.

To a solution of freshly distilled diisopropylamine (131.0 mL, 0.936 mole, 1.5 equiv.) In dry THF (1400 mL) was added dropwise a solution of n-BuLi (2.5 M in hexanes) (374 , 4 mL, 0.936 mole, 1.5 equiv.) At -20 ° C under argon. The reaction mixture was stirred for 5 minutes at -20 ° C. Then, a solution of 2-cycloheksen-1-one (60 g, 0.624 mol, 1 equiv) was added dropwise and the reaction mixture was stirred for 25 minutes at -20 ° C. After that time, a solution of DMAP (3.8 g, 0.031 mol, 0.05 equiv.) In 30 mL of THF was added, and then ethyl chloroformate (71 mL, 0.749 moles, 1.2 equiv.) at -20 ° C. The resulting reaction mixture was stirred for 1h at -20 ° C, then allowed to warm to room temperature and stirred for 1h at room temperature. The mixture was washed with a saturated NH4Cl solution (3 x 600 mL), brine (1 x 200 mL), dried over MgSO4, filtered, and concentrated in vacuo. To remove THF contamination, the solution was evaporated from hexane (2 x 200 mL). The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 20: 1 to 4: 1) to provide ethyl 2-oxocyclohex-3-enecarboxylate (71.79g, 68%, yellow liquid) . ESI + MS: m / z = 169.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.02 - 6.98 (m, 1H), 6.07 (dt, J = 10.1, 2.0 Hz, 1H), 4.25 - 4.18 (m, 2H), 3.41-3.38 (m, 1H), 2.54-2.46 (m, 1H), 2.44-2.33 (m, 2H), 2.26-2 , 18 (m, 1H), 1.28 (t, J = 7.2, 3H).

Step B. Ethyl 2-Hydroxy-4-vinylcyclohex-1-ene-1-carboxylate.

A solution of vinylmagnesium bromide (1M in THF) (119 mL, 0.119 mol, 2 equiv.) And HMPA (41.6 mL) was added dropwise to a suspension of CuBrxMe2S (1.83 g, 8.92 mmol , 0.15 equiv.) In dry THF (250 mL) at -78 ° C for 15 min under argon. After stirring at -78 ° C for 15 min, a solution of ethyl 2-oxocyclohex-3-ene-1-carboxylate (10 g, 59.5 mmol, 1.0 equiv.) And TMSCl were added dropwise (37.7 mL, 0.297 mol, 5 equiv.) In dry THF (100 mL) (over 30 min). The reaction mixture was stirred at -78 ° C for 2h. The mixture was then quenched with saturated aqueous NH4Cl.

(200 mL) and washed with AcOEt (3 x 150 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (hexane / AcOEt 10: 1) to provide ethyl 2-hydroxy-4-vinylcyclohex-1-ene-1-carboxylate (4.94 g, 42%) as a light yellow liquid. 1H NMR (700 MHz, chloroform-d) 55.91 -5.70 (m, 1H), 5.16-4.90 (m, 2H), 4.22 (qd, J = 7.1, 0, 5Hz, 2H), 2.45-2.30 (m, 3H), 2.24-2.12 (m, 2H), 1.89-1.74 (m, 1H), 1.45-1 , 18 (m, 5H).

Step C. ethyl rac- (1R, 2R, 4R) -2-Acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate.

To the stirred solution of ethyl 2-hydroxy-4-vinylcyclohex-1-ene-1-carboxylate (3.8 g, 19.3 mmol, 1 equiv.) And ammonium acetate (5.95 g, 77.2 mmol, 4 equiv.) in 2,2,2-trifluoroethanol (70 mL), tert- butyl isocyanide was added dropwise

(4.38 mL, 38.7 mmol, 2 equiv.) Via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 2: 1) to provide 3.66 g (56%) of the corresponding product as a white solid. ESI + MS: m / z = 339.1 (M + 1) +, 361.1 (M + Na) +. 1H NMR (700 MHz, chloroform-d) 58.10 (s, 1H), 7.57 (s, 1H), 5.72 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H ), 5.03 - 4.91 (m, 2H), 4.20 (ddq, J = 59.5, 10.8, 7.1 Hz, 2H), 3.29 (d, J = 13.8 Hz, 1H), 2.28 (dd, J = 12.4, 4.4 Hz, 1H), 2.14 (dq, J = 11.6, 4.2, 3.6 Hz, 1H), 2 , 11-2.02 (m, 2H), 1.99 (s, 3H), 1.85-1.80 (m, 1H), 1.33-1.30 (m, 13H), 1.10 (qd, J = 13.2, 4.4 Hz, 1H).

Intermediate 2. Ethyl (1R, 2R, 4R) - (+) - 2-Acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate.

Step A. (4R) - (+) - Ethyl 4-Ethenyl-2-hydroxycyclohex-1-ene-1-carboxylate.

Rh (cod) 2BF4 (2.74 g, 6.75 mmol, 0.033 equiv.), (R) -BINAP (4.20 g,

6.75 mmol, 0.033 equiv.) And potassium vinyl trifluoroborate (63.70 g, 475.6 mmol, 2.0 equiv.). The reaction flask was flushed with argon several times and degassed EtOH (2,000 mL) was added along with triethylamine (100.30 mL, 713.4 mmol, 3.0 equiv.). After stirring the reaction mixture for 15 min at room temperature, ethyl 2-oxocyclohex-3-enecarboxylate (50 g, 297 mmol) was added. The reaction mixture was stirred for 3 days at room temperature under argon. The EtOH was evaporated in vacuo and the crude reaction mixture was poured into EtOAc (800mL) and washed with 40% brine in 0.5M HClac (3 x 800mL). The combined organic layers were washed with brine (1 x 100mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 30: 1 to 5: 1) to provide ethyl (4R) - (+) - 2-oxo-4-vinylcyclohexanecarboxylate (15, 5 g, 25%, yellow liquid). ESI + MS: m / z = 197.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 12.21 (s, 1H), 5.85 -5.78 (m, 1H), 5.07 - 4.99 (m, 2H), 4.25 - 4.18 (m, 2H), 2.41-2.33 (m, 2H), 2.27-2.13 (m, 2H), 1.85-1.79 (m, 1H), 1, 60-1.52 (m, 1H), 1.41-1.32 (m, 1H), 1.32-1.25 (m, 3H).

Step B. Ethyl (1R, 2R, 4R) - (+) - 2-Acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate.

To the stirred solution of ethyl (4R) - (+) - 4-ethenyl-2-hydroxycyclohex-1-ene-1-carboxylate (8.2 g, 41.78 mmol, 1 equiv.) And ammonium acetate ( 12.88 g, 167.13 mmol, 4 equiv.) In 2,2,2-trifluoroethanol (164 mL), tert-butyl isocyanide (9.4 mL, 83.57 mmol, 2 equiv. .) via syringe and the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (250 mL) and washed with water (50 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 15: 1 to 3: 1) to provide 7.04 g (50%) of the corresponding product as a single enantiomer (> 99.5% ee) as a white solid. ESI + MS: m / z = 339.1 (M + 1) +, 361.1 (M + Na) +. [a] D = 57.6 (c = 1.0 in CHCla). 1H NMR (700 MHz, Chloroform-cf) 58.13 (s, 1H), 7.60 (s, 1H), 5.75 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H ), 5.06 - 4.93 (m, 2H), 4.23 (ddq, J = 59.6, 10.8, 7.1 Hz, 2H), 3.32 (dt, J = 13.9 , 2.6 Hz, 1H), 2.31 (dd, J = 12.4, 4.4 Hz, 1H), 2.20 - 2.05 (m, 2H), 2.02 (s, 3H) , 1.88-1.84 (m, 1H), 1.60-1.56 (m, 1H), 1.37 (dd, J = 13.9, 12.7 Hz, 1H), 1.33 (s, 9H), 1.32-1.30 (m, 3H), 1.13 (tdd, J = 13.3, 12.0, 4.4 Hz, 1H). The enantiomeric excess was determined by chiral HPLC using a RegisPack 250 / 4.6 mm, 5 ^ column eluted with 1 mL / min flow of 10% isopropanol in hexane.

Examples:

Comparative Example 1. 1-Amino-3- (2-boronoethyl) cyclopentane-1-carboxylic acid hydrochloride

Step A. 1-Acetamido-N- (tert-butyl) -3-vinylcyclopentane-1-carboxamide.

To a stirred solution of 3-vinylcyclopentan-1-one (0.60 g, 5.45 mmol) (prepared from 2-cyclopenten-1-one using a literature method. J. Am. Chem. Soc. , 103, (1981) 476-477) and ammonium acetate (1.68 g, 21.79 mmol) in 2,2,2-trifluoroethanol (1.5 mL), tert-butyl isocyanide (1, 23 mL, 10.9 mmol) via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 15 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated under reduced pressure . The residue was triturated with diethyl ether (2 mL) and hexane (2 x 2mL) to provide 0.85 g (62%) of the desired product as a white solid (mixture of diastereoisomers, 1.4: 1). ESI + MS: m / z = 275.2 (M + Na) +, ESI-MS: m / z = 251.2 (M-1) -. 1H NMR (700 MHz, CDCls) 5 7.00 (bs, 1H, single diastereoisomer), 6.88 (bs, 1H, single diastereoisomer), 5.90 -5.77 (m, 2H), 5.02 - 5.07 (m, 1H), 4.99-4.92 (m, 1H), 2.81-2.75 (m, 1H, single diastereoisomer), 2.74-2.68 (m, 1H, single diastereoisomer), 2.65 (d, J = 13.4, 1H, single diastereoisomer), 2.64 (d, J = 13.4, 1H, single diastereoisomer) 2.43-2.36 (m, 1H ), 2.25-2.30 (m, 1H), 2.07-1.94 (m, 5H), 1.73 (dd, J = 13.4, 8.9 Hz, 1H), 1, 64-1.54 (m, 1H), 1.35 (s, 9H).

Step B. 1-Acetamido-N- (tert-butyl) -3-methyl-3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane -1-carboxamide.

A round bottom flask filled with bis (1,5-cyclooctadiene) diiridium (I) dichloride (64 mg, 0.095 mmol), 1,2-bis (diphenylphosphino) ethane (76 mg, 0.19 mmol) and dry CH2Cl2 (10 mL) was purged with argon (bubbling). Subsequently, a separately prepared solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.69 mL, 4.75 mmol), 1-acetamido-N- (ferf-butyl) was added successively -3-vinylcyclopentane-1-carboxamide (0.80 g, 3.17 mmol) in 5 mL of dry CH2Cl2 at room temperature. The resulting light yellow mixture was then stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel (using EtOAc-hexane, 1: 2 to 1: 1 as the eluent) to yield 0.98 g (81%) of the desired product as a viscous white solid (mixture of diastereoisomers 1.5: 1). ESI + MS: m / z = 381.2 (M + H) +, 403.2 (M + Na) +, ESI-MS: m / z = 379.3 (M-1) -. 1H NMR (700 MHz, CDCI3) 56.97 (bs, 1H, single diastereoisomer), 6.91 (bs, 1H, single diastereoisomer), 5.89 ( bs, 1H, single diastereoisomer), 5.69 (bs, 1H, single diastereoisomer), 2.57 (dd, J = 13.5, 8.2 Hz, 1H, single diastereoisomer), 2.36-2.28 (m, 1H), 2.22 (dd, J = 13.7, 7.1 Hz, 1H, single diastereoisomer), 2.01 (s, 3H, single diastereoisomer), 2.00 (s, 3H, diastereoisomer single), 1.98-1.91 (m, 3H), 1.79 (dd, J = 13.7, 10.5 Hz, 1H, single diastereoisomer), 1.53-1.46 (m, 2H ), 1.338 (s, 9H, single diastereoisomer), 1.340 (s, 9H, single diastereoisomer), 1.261 (s, 12H, single diastereoisomer), 1.259 (s, 12H, single diastereoisomer), 0.91 (td, J = 7.4, 1.1 Hz, 1H, single diastereoisomer), 0.84-0.74 (m, 2H).

Step C. 1-Amino-3- (2-boronoethyl) cyclopentane-1-carboxylic acid hydrochloride.

A mixture of 1-acetamido-N- (tert-butyl) -3-methyl-3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane -1-carboxamide (200 mg, 0.53 mmol) and 10 mL of 6N HCl (aq) was refluxed overnight. After concentrating in vacuo, the residue was subjected to preparative HPLC chromatography (0.1-2% gradient elution, acetonitrile-water). Overall yield of possible isolated stereoisomers of the target product (96 mg, 77%).

The diastereoisomers were partially separated as the following diastereoisomeric ratios: trans / cis = 9: 1 (5 mg; white solid). ESI + MS: m / z = 202.1 (M + H) +, ESI-MS: m / z = 200.1 (M-1) -. 1H NMR (700 MHz, D2O) (major trans-diastereoisomer) 52.39 (dd, J = 13.9, 7.9 Hz, 1H), 2.17 (ddd, J = 14.1, 12.0, 7.5 Hz, 1H), 2.10 -2.05 ( m, 1H), 2.02-1.96 (m, 1H), 1.91 (dd, J = 14.4, 7.6 Hz, 1H), 1.45 (dd, J = 15.4, 7.8 Hz, 2H), 1.33 (dt, J = 14.0, 7.8 Hz, 2H), 0.76 (td, J = 7.7, 3.2 Hz, 2H).

trans / cis = 1: 1 (58 mg; white solid). ESI + MS: m / z = 202.1 (M + H) +, ESI-MS: m / z = 200.1 (M-1) -. 1H NMR (700 MHz, D2O) (minor cis-diastereoisomer) 52.37 (ddd, J = 14.3, 8.9, 3.5 Hz, 1H), 2.13-2.06 (m, 2H), 2.03-1.99 (m, 1H), 1.90 (dd, J = 13.6, 10.2 Hz, 1H), 1.88-1.82 (m, 1H), 1.48 (ddd, J = 11.4, 6.0, 2 , 0 Hz, 3H), 0.79-0.74 (m, 2H).

Comparative Example 2. Rac- (2S, 3R) -1-amino-3- (2-boronoethyl) -2-methylcyclopentane-1-carboxylic acid hydrochloride.

Step A. rac- (2S, 3S) -1-Acetamido-N- (tert-butyl) -2-methyl-3-vinylcyclopentane-1-carboxamide.

To a stirred solution of 2-methyl-3-vinylcyclopentan-1-one (1.20 g, 9.7 mmol, 1 equiv.) (Dr = 14: 1; prepared from 2-methyl-2-cyclopenten- 1-one using a method from the literature. J. Am. Chem. Soc., 103, (1981) 476-477) and ammonium acetate (2.98 g, 38.7 mmol, 4 equiv.) At 2, 2,2-trifluoroethanol (3 mL), tert-butyl isocyanide (1.60 g, 2.17 mL, 19.4 mmol, 2 equiv.) Was added via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (using AcOEthexane, 1:10 as the eluent) to provide 1-acetamido-N- (tert-butyl) -2-methyl-3-vinylcyclopentane-1-carboxamide as a mixture. of two, of four possible, diastereoisomers in a 2.5: 1 ratio (0.40 g, 16%, light yellow oil). ESI + MS: m / z = 289.1 (M + Na) +, ESI-MS: m / z = 265.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 5.74 -5.62 (m, 1H), 5.10-4.95 (m, 2H), 2.50 (dt, J = 14.3, 9.0 Hz, 1H), 2.34-2.22 (m, 1H), 2.02 (s, 3H), 1.79-1.68 (m, 1H), [1.37, 1.35 (2s, 9H, two diastereoisomers)], 1.27 ( m, 3H), [0.97, 0.96 (2d, J = 6.8, J = 6.6 Hz, 3H, two diastereoisomers)].

Step B. rac- (2S, 3R) -1-Acetamido-N- (fe / 'c-butyl) -2-methyl-3- (2- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) ethyl) cidopentane-1-carboxamide.

A round bottom flask filled with bis (1,5-acid-octadiene) diiridium (I) dichloride (15 mg, 0.022 mmol, 0.03 equiv.), 1,2-bis (diphenylphosphino) ethane (18 mg, 0.044 mmol , 0.06 equiv.) And dry CH2Cl2 (5 mL) was purged with argon (sparging). Subsequently, the separately prepared solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.24 g, 0.30 mL, 1.88 mmol, 2.5 equiv.) Was added successively, 1-acetamido-N- (fe / 'c-butyl) -2-methyl-3-vinylcyclopentane-1-carboxamide (0.20 g, 0.75 mmol, 1 equiv.) In 5 mL of dry cH2Cl2 at room temperature . The resulting light yellow mixture was then stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel (using AcOEt-hexane, 1:10 as the eluent) to yield 1-acetamido-N- (fe / 'c-butyl) - 2-methyl-3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide target as a mixture of diastereoisomers, dr = 2, 5: 1 (0.21 g, 72%, sticky light yellow oil). ESI + MS: m / z = 395.1 (M + H) +, ESI-MS: m / z = 393.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 52.36-2.28 (m, 1H), 2.11-1.95 (m, 2H), [2.05, 2.00 (2s, 3H, two diastereoisomers)], 1.95-1.84 (m, 1H), 1.69-1.57 (m, 3H), 1.48-1.38 (m, 1H), [1.36, 1, 35 (2s, 9H, two diastereoisomers)], [1.28, 1.25 (2s, 12H, two diastereoisomers)], [0.99, 0.95 (2d, J = 7.30 Hz, J = 7 , 17 Hz, 3H, two diastereoisomers)], 0.91-0.82 (m, 1H), 0.78-0.71 (m, 1H).

Step C. Rac- (2S, 3R) -1-Amino-3- (2-boronoethyl) -2-methylcyclopentane-1-carboxylic acid hydrochloride.

A mixture of 1-acetamido-N- (fe / 'c-butyl) -2-methyl-3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Ethyl) cyclopentane-1-carboxamide (211 mg, 0.54 mmol) and 20 mL of 6N HCl (aq) was refluxed for 6 hours. After concentrating in vacuo, the residue was subjected to preparative HPLC chromatography (0.1-2% gradient elution, acetonitrile-water). Overall yield of possible isolated stereoisomers of a target product (47 mg, 35%).

A single diastereoisomer with unknown configuration in the amino acid residue separated. Furthermore, the mixture of diastereoisomers (dr 1: 1) was also isolated.

Single diastereoisomer (28 mg, 21%, white solid) ESI + MS: m / z = 216.1 (M + H) +, ESI-MS: m / z = 196.1 (M-18-1) - 1H NMR (700 MHz, D2O) at 2.29 (dt, J = 14.6, 8.9 Hz, 1H), 1.98-1.93 (m, 1H), 1.83-1.76 (m , 1H), 1.67-1.55 (m, 3H), 1.36-1.28 (m, 1H), 1.15-1.02 (m, 1H), 0.90 (d, J = 6.3 Hz, 3H), 0.77-0.70 (m, 1H), 0.66-0.59 (m, 1H).

Mixture of diastereoisomers (dr = 1: 1) (19 mg, 14%, white solid). ESI + MS: m / z = 215.9 (M + H) + ESI-MS: m / z = 196.0 (M-18-1) - 1H NMR (700 MHz, D2O) 52.32-2, 26 (m, 1H), 2.03-1.89 (m, 1H), 1.80-1.73 (m, 1H), 1.65-1.48 (m, 3H), 1.41 - 1.28 (m, 1H), 1.17-1.09 (m, 1H), [0.90, 0.87 (2d, J = 7.2 Hz, J = 6.8 Hz, 3H, two diastereoisomers)], 0.76-0.70 (m, 1H), 0.66-0.60 (m, 1H).

Comparative Example 3. 1-Amino-3- (2-boronoethyl) -3-methylcidopentane-1-carboxylic acid hydrochloride.

Step A. 3-Methyl-3-vinylcidopentan-1-one.

A solution of vinylmagnesium bromide (1M in THF) (32 mL, 32 mmol) and HMPA (11.13 mL, 64 mmol) were added separately dropwise to a suspension of CuBr x Me2S (802 mg, 3.9 mmol ) in dry THF (100 mL) at -78 ° C under argon for 10 min. After stirring at -78 ° C for 15 min, a solution of 3-methyl-2-cyclopenten-1-one (1.58 mL, 16 mmol) and TMSCl (10.15 mL, 80 mmol) were added dropwise ) in dry THF (35 mL) for 30 min. The reaction mixture was stirred at -78 ° C for 2 h. The mixture was then slowly warmed to RT and stirred at temperature overnight. The mixture was then quenched with saturated aqueous NH4Cl (100 mL) and washed with AcOEt (3 x 150 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (hexane / AcOEt 25: 1 to 20: 1) to provide 3.0 g (100%) of a desired product as a yellow liquid (contained approximately 20% hexane) . 1H NMR (700 MHz, chloroform-d) 55.91 (dd, J = 17.4, 10.7 Hz, 1H), 5.08 - 4.94 (m, 2H), 2.38 - 2.33 (m, 1H), 2.31 (t, J = 7.8 Hz, 2H), 2.10 (d, J = 18.3 Hz, 1H), 2.03-1.97 (m, 1H) , 1.84 (dtd, J = 12.9, 7.9, 1.2 Hz, 1H), 1.22 (s, 3H).

Step B. 1-Acetamido-N- (tere-butyl) -3-methyl-3-vinylcyclopentane-1-carboxamide.

To a mixture of 3-methyl-3-vinylcyclopentan-1-one (2.9 g, 23.35 mmol), ammonium acetate (7.2 g, 93.4 mmol), 2,2,2-trifluoroethanol ( 5.7 mL) tere-butyl isocyanide (5.25 mL, 46.70 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was then quenched with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (hexane / AcOEt 90: 1 to 70: 1). Single diastereoisomers (250 mg and 920 mg) were separated. Overall yield: 1.17g (19%).

Single diastereoisomer 1 (250mg, yellow oil); ESI + MS: m / z = 289.1 (M + Na) +, 267.2 (M + 1) +, ESI-MS: m / z = 265.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 55.94 (dd, J = 17.4, 10.7 Hz, 1H), 5.03 - 4.94 (m, 2H), 2.50 (dt, J = 13.6 , 8.0 Hz, 1H), 2.28 (d, J = 14.3 Hz, 1H), 2.16-2.09 (m, 1H), 1.99 (s, 3H), 1.91-1.82 (m, 1H), 1.64 (ddd, J = 13.2, 7.9, 5.9 Hz, 2H), 1.34 (s, 9H), 1.17 (s, 3H).

Single diastereoisomer 2 (920 mg, white solid; ESI + MS: m / z = 289.1 (M + Na) +, 267.2 (M + 1) +, ESI-MS: m / z = 265.2 ( M-1) -. 1H NMR (700 MHz, chloroform-d) 55.94 (dd, J = 17.5, 10.7 Hz, 1H), 5.13-4.89 (m, 2H), 2 , 47-2.44 (m, 1H), 2.44-2.40 (m, 1H), 2.04 (d, J = 5.2 Hz, 1H), 2.02 (s, 3H), 2.01 (s, 1H), 1.89-1.84 (m, 1H), 1.79 (dt, J = 12.9, 7.7 Hz, 1H), 1.34 (s, 9H) , 1.21 (s, 3H).

Step C. 1-Acetamido-N- (fe / 'c-butyl) -3-methyl-3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide.

A mixture of dppe (20.5 mg, 0.052 mmol), bis (1,5-cyclooctadiene) diiridium (I) dichloride (17 mg, 0.026 mmol) was dissolved in dichloromethane (3 mL) and purged with argon (bubbling ). A solution of 1-acetamido-N- (fe / 'c-butyl) -3-methyl-3-vinylcyclopentane-1-carboxamide (230 mg, 0.86 mmol) and a pinacolborane in DCM (3 mL) (argon purged) (162 ^ L, 1.12 mmol). The reaction mixture was stirred at room temperature for 3 days. After that time, the crude product was purified by column chromatography, on silica gel (hexane / AcOEt 5: 1 to 2: 1) to provide the desired product (170 mg, 50%) as a yellow oil. ESI + MS: m / z = 395.1 (M + 1) +, 335.1. ESI-MS: m / z = 393.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 52.45-2.39 (m, 1H), 2.15 (d, J = 14 , 4Hz, 1H), 2.02 (s, 3H), 1.84 (d, J = 14.4Hz, 1H), 1.66-1.57 (m, 4H), 1.55-1 , 49 (m, 1H), 1.49-1.45 (m, 1H), 1.39 (d, J = 30.7 Hz, 1H), 1.29

(s, 9H), 1.28-1.26 (m, 12H), 0.88 (t, J = 7.1 Hz, 1H), 0.77 (ddd, J = 9.7, 6.8 , 2.9 Hz, 2H).

The second diastereoisomer was obtained in the same way starting from 0.92 g (3.45 mmol) of 1-acetamido-N- (fe / 'c-butyl) -3-methyl-3-vinylcyclopentane-1-carboxamide . The crude product was purified by silica gel flash column chromatography (hexane / AcOEt 2: 1 to 1: 1) to provide 1.2 g (88%) of the desired product as a yellow oil. ESI + MS: m / z = 395.1 (M + 1) +. ESI-MS: m / z = 393.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 52.39 (dt, J = 13.5, 7.8 Hz, 1H), 2, 20 (d, J = 14.4 Hz, 1H), 2.01 (s, 3H), 1.97-1.92 (m, 1H), 1.87 (d, J = 14.2 Hz, 1H ), 1.67-1.60 (m, 1H), 1.52-1.43 (m, 3H), 1.33 (s, 9H), 1.25 (s, 12H), 1.03 ( s, 3H), 0.77-0.70 (m, 2H).

Step D. 1-Amino-3- (2-boronoethyl) -3-methylcyclopentane-1-carboxylic acid hydrochloride.

A mixture of 1-acetamido-N- (fe / 'c-butyl) -3-methyl-3-vinylcyclopentane-1-carboxamide (90 mg, 0.23 mmol) and 6 N HCl (aq)

(1 mL) was refluxed 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.1-2% MeCN in water) to provide the desired product (20 mg, 25%) as a white solid. ESI + MS: m / z = 216.1 (M + 1) +, ESI-MS: m / z = 196.1 (M-18-1) -. 1H NMR (700 MHz, deuterium oxide) 52, 46

(dt, J = 14.4, 9.2 Hz, 1H), 2.19 (d, J = 15.1 Hz, 1H), 1.99 (dt, J = 14.4, 5.5 Hz, 1H), 1.76-1.67 (m, 3H), 1.48 (t, J = 8.5 Hz, 2H), 1.03 (s, 3H), 0.78-0.66 (m , 2H).

The second diastereoisomer was obtained in the same way starting from 200 mg (0.51 mmol) of 1-acetamido-N- (fe / 'c-butyl) -3-methyl-3-vinylcyclopentane-1-carboxamide. The crude product was purified by preparative HPLC (0.1-4% MeCN in water) to provide the desired product (50mg, 28%) as a white solid. ESI + MS: m / z = 216.1 (M + 1) +, ESI-MS: m / z = 214.1 (M-1) -. 1H NMR (700 MHz, deuterium oxide) 52.37 ( dt, J = 14.3, 7.2 Hz, 1H), 2.29 (d, J = 15.1 Hz, 1H), 2.04 (dt, J = 14.3, 7.3 Hz, 1H ), 1.84-1.76 (m, 1H), 1.70-1.59 (m, 2H), 1.48 (t, J = 8.5 Hz, 2H), 1.04 (s, 3H), 0.76-0.65 (m, 2H).

Comparative Example 4. Rac- (1S, 3S, 4S) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid hydrochloride

Step A. rae- (3S, 4R) -3 - ((tere-Butyldimethylsilyl) oxy) -4-vinylcyclopentan-1-one.

To a suspension of CuBr x Me2S (802 mg, 3.9 mmol) in tetrahydrofuran (100 mL), vinylmagnesium bromide (1 M in tetrahydrofuran) (32 mL, 32.0 mmol) was added dropwise under Ar at -78 ° C. Then HMPA (11.1 mL,

64.0 mmol) and stirred for 10 min. A solution of 4 - [(erc-butyldimethylsilM) oxy] cyclopent-2-en-1-one (3.4 g, 16.0 mmol), TMSCl (10.2 mL, 80.0 mmol) was added dropwise ) in tetrahydrofuran (35 mL) for 30 min. The resulting mixture was stirred at -78 ° C for 30 min, then between -75 ° C and -45 ° C for 25 min. The mixture was quenched with NH4Cl (sat.) And extracted with ethyl acetate three times. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography (20: 1 to 10: 1 hexane / diethyl ether) to yield 1.4 g (36%) of the desired product as a light yellow oil. 1H NMR (700 MHz, CDCls) 55.86 -5.77 (m, 1H), 5.14 -5.07 (m, 2H), 4.14 (q, J = 6.1 Hz, 1H), 2.81 (p, J = 7.6 Hz, 1H), 2.61-2.49 (m, 2H), 2.22-2.16 (m, 1H), 2.11 (dd, J = 18.4, 8.1 Hz, 1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). Step B. rae- ( 1 R, 3S, 4R) - and rae- (1S, 3S, 4R) -1-Acetamido-N- (tere-butyl) -3 - ((tere-butyldimethylsilyl) oxy) -4- vinylcyclopentane-1-carboxamide.

To a stirred solution of rae- (3S, 4R) -3 - ((tere-butyldimethylsilyl) oxy) -4-vinylcyclopentan-1-one (1.3 g, 5.4 mmol) and ammonium acetate (1.66 g, 21.6 mmol) in 2,2,2-trifluoroethanol (1.5 mL), tere-butyl isocyanide (1.22 mL, 10.8 mmol) via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 15 mL) and brine (20 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. . The crude product was purified by silica gel flash chromatography. (hexane / ethyl acetate 2: 1 to 1: 1) to yield 60 mg (3%) of rac- (1R, 3S, 4R) -1-acetamido-N- (tert-butyl) -3 - ((tert -butyldimethylsilyl) oxy) -4-vinylcyclopentane-1-carboxamide as a white solid and 130 mg (6%) of rac- (1S, 3S, 4R) -1-acetamido-N- (tert-butyl) -3- ( (tert-butyldimethylsilyl) oxy) -4-vinylcyclopentane-1-carboxamide as a white solid.

Rac- (1R, 3S, 4R) isomer: ESI + MS: m / z = 383.2 (M + H) +, 405.1 (M + Na) +, ESI-MS: m / z = 381.2 (M-1) -. 1H NMR (700 MHz, CDCls) 56.88 (bs, 1H), 6.20 (bs, 1H), 5.76 (ddd, J = 17.1, 10.2, 8.0 Hz, 1H), 5.08 - 4.97 (m, 2H), 4.03 (ddd, J = 7.1,4.3, 3.1 Hz, 1H), 2.65-2.58 (m, 1H), 2.50 (dd, J = 14.2, 6.7 Hz, 1H), 2.46 (ddd, J = 13.9, 7.8, 2.3 Hz, 1H), 2.06 (dd, J = 14.0, 10.3 Hz, 1H), 2.01 (s, 3H), 1.79 (dt, J = 14.2, 2.5 Hz, 1H), 1.32 (s, 9H ), 0.89 (s, 9H), 0.05 (s, 6H). Rac- (1S, 3S, 4R) isomer: ESI + MS: m / z = 383.2 (M + H) +, 405.1 (M + Na) +, ESI-MS: m / z = 381.2 (M-1) -. 1H NMR (700 MHz, CDCls) 56.84 (bs, 1H), 6.45 (bs, 1H), 5.84 (ddd, J = 17.2, 10.2, 8 , 0 Hz, 1H), 5.09 -5.00 (m, 2H), 4.24 (ddd, J = 8.1.5.9, 4.8 Hz, 1H), 2.87 (dd, J = 14.9, 8.1 Hz, 1H), 2.62-2.54 (m, 1H), 2.28 (dd, J = 13.5, 8.1 Hz, 1H), 2.09 (ddd, J = 19.2, 14.2, 7.6 Hz, 2H), 1.97 (s, 3H), 1.36 (s, 9H), 0.88 (s, 9H), 0, 07 (s, 3H), 0.06 (s, 3H).

Step C. rac- (1 S, 3S, 4S) -1-Amino-N- (tert-butyl) -3-hydroxy-4- (2- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide and rac- (1R, 3S, 4S) -1-amino-N- (tert-butyl) -3-hydroxy-4- (2- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide.

Title compounds were prepared from rac- (1S, 3S, 4R) - and rac- (1R, 3S, 4R) -1-acetamido-N- (tert-butyl) -3 - ((tert-butyldimethylsilyl ) oxy) -4-vinylcyclopentane-1-carboxamide respectively using the procedure described for the preparation of Comparative Example 1, step B.

The crude product was purified by silica gel flash chromatography. (20: 1 to 1: 1 hexane / ethyl acetate). Obtained: rac- (1S, 3S, 4S) isomer: 24 mg (36%). ESI + MS: m / z = 511.2 (M + H) +, 533.2 (M + Na) +, ESI-MS: m / z = 509.2 (M-1) -. 1H NMR (700 MHz, CDCh) 56.88 (bs, 1H), 6.50 (bs, 1H), 4.16 (dt, J = 12.0, 3.8 Hz, 1H), 2.88 (dd, J = 15.0, 7.9 Hz, 1H), 2.27 (dd, J = 12.2, 6.8 Hz, 1H), 2.07 (dd, J = 15.0, 3.8 Hz, 1H ), 1.98 (s, 3H), 1.97-1.94 (m, 1H), 1.81-1.74 (m, 1H), 1.57 (s, 9H), 1.48 - 1.40 (m, 1H), 1.37 (s, 9H), 1.30-1.28 (m, 1H), 1.26 (s, 12H), 0.92 (s, 9H), 0 , 85 - 0.73 (m, 2H), 0.12 (s, 3H), 0.11

(s, 3H).

Obtained:

rac- (1R, 3S, 4S) isomer: 27 mg (38%). ESI + MS: m / z = 511.2 (M + H) +, ESI-MS: m / z = 509.2 (M-1) -. 1H NMR (700 MHz, CDCh) 56.90 (bs, 1H), 6.41 (bs, 1H), 4.01-3.96 (m, 1H), 2.53 (ddd, J = 13.8, 7.8, 2.4 Hz, 1H), 2 , 38 (dd, J = 14.2, 6.2 Hz, 1H), 2.00 (s, 3H), 1.81-1.76 (m, 2H), 1.71-1.64 (m , 1H), 1.58 (s, 9H), 1.39-1.36 (m, 1H), 1.35 (s, 9H), 1.29-1.27

(m, 1H), 1.26 (s, 12H), 0.79 (ddd, J = 16.7, 9.7, 6.2 Hz, 2H), 0.11 (s, 3H), 0, 10 (s, 3H).

Step D. Rac- (1S, 3S, 4S) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid hydrochloride.

The title compound was prepared from rac- (1S, 3S, 4S) -1-amino-N- (tert-butyl) -3-hydroxy-4- (2- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide using the procedure described for the preparation of the Comparative Example 1, step C. The crude product was subjected to preparative HPLC chromatography (0.1-2% MeCN) to yield

3 mg (27%) of the desired product. ESI + MS: m / z = 218.0 (M + H) +, 200.0 (M-18 + H) +, ESI-MS: m / z = 198.0 (M-18-1) -.

1H NMR (700 MHz, D2O) 53.95 (dd, J = 17.0, 8.9 Hz, 1H), 2.49 (dd, J = 14.0, 7.7 Hz, 1H), 2, 29 (dd, J = 14.4, 7.6 Hz, 1H), 2.23 (dd, J = 14.4, 9.2 Hz, 1H), 2.04-1.95 (m, 1H) , 1.77-1.59 (m, 1H), 1.45 (dd, J = 14.1, 11.6 Hz, 1H), 1.42-1.32

(m, 1H), 0.88-0.72 (m, 2H).

Comparative Example 5. Rac- (1R, 3S, 4S) -1-amino-3- (2-boronoethyl) -4-hydroxycyclopentane-1-carboxylic acid hydrochloride

The title compound was prepared from rac- (1R, 3S, 4S) -1-amino-N- (tert-butyl) -3-hydroxy-4- (2- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) ethyl) cidopentane-1-carboxamide using the procedure described for the preparation of Comparative Example 1, step C. The crude product was subjected to preparative HPLC chromatography (0.1 MeCN - 2%) to yield

9 mg (82%) of the desired product. ESI + MS: m / z = 218.0 (M + H) +, ESI-MS: m / z = 216.1 (M-1) -. 1H NMR (700 MHz, D2O) 54.07 (q, J = 6.6 Hz, 1H), 2.55 (dd, J = 14.2, 6.4 Hz, 1H), 2.21 (dd, J = 14.1, 7.4 Hz, 1H), 2.02-1.95 (m, 1H), 1.93

(dd, J = 14.2, 9.9 Hz, 1H), 1.84 (dd, J = 14.2, 6.8 Hz, 1H), 1.70-1.56 (m, 1H), 1.45-1.34 (m, 1H), 0.87-0.72 (m, 2H). Comparative Example 6. Rac- (1S, 3S, 4S) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid dihydrochloride

Step A. 4-Vinylcyclopent-2-en-1-one.

To a suspension of CuBr x Me2S (2.33 g, 11.32 mmoles) in tetrahydrofuran (300 mL), vinylmagnesium bromide (1 M in tetrahydrofuran) (94 mL, 94.34 mmol) was added dropwise under Ar to -78 ° C. Then HMPA (32.8 mL, 188.68 mmol) was added and stirred for 10 min. A solution of

- ((tert-butyldimethylsilyl) oxy) cyclopent-2-en-1-one (10 g, 47.17 mmol), TMSCl (30 mL, 235.85 mmol) in tetrahydrofuran (100 mL) for 15 min. The resulting mixture was stirred at -78 ° C for 30 min, then between -60 ° C - 25 ° C for 30 min. The mixture was quenched with NH4Cl (sat.) And extracted with ethyl acetate three times. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography (20: 1 to 2: 1 hexane / diethyl ether) to provide 2.13 g (42%) of the desired product as a colorless oil. ESI + MS: m / z = 131.9 (M + Na) +, 108.7 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 6 7.57 (dt, J = 4.8, 2.4 Hz, 1H), 6.24 - 6.17 (m, 1H), 5.81 -5, 69 (m, 1H), 5.20-5.08 (m, 2H), 2.65 (dtd, J = 18.8, 4.0, 2.0 Hz, 1H), 2.21-2, 14 (m, 1H), 1.84 (dd, J = 7.1, 3.1 Hz, 1H).

Step B. rac- (3S, 4R) -3- (Nitromethyl) -4-vinylcyclopentan-1-one.

To the solution of 4-vinylcyclopent-2-en-1-one (550 mg, 5.1 mmol) in nitromethane (4.1 mL, 76.3 mmol) at 0 ° C, 7 drops of DBU were added. The reaction mixture was stirred at rt for 2 days. The mixture was diluted with diethyl ether and washed with 1M HCl, water, and brine. It was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography (20: 1 to 5: 1 hexane / ethyl acetate) to provide 110 mg (13%) of the desired product as a colorless oil. 1H NMR (700 MHz, chloroform-d) 55.79 -5.72 (m, 1H), 5.29 -5.17 (m, 2H), 4.65 (dd, J = 12.8, 4, 3Hz, 1H), 4.38 (dd, J = 12.8, 9.1Hz, 1H), 2.80-2.71 (m, 1H), 2.68 (dd, J = 18.3 , 7.7 Hz, 1H), 2.64-2.55 (m, 2H), 2.26-2.18 (m, 1H), 2.18-2.11 (m, 1H).

Step C. rae- (1S, 3S, 4R) - and rae- (1R, 3S, 4R) -1-Acetamido-N- (tere-butyl) -3- (nitromethyl) -4-vinylcyclopentane-1-carboxamide.

To a mixture of rae- (3S, 4R) -3- (nitromethyl) -4-vinylcyclopentan-1-one (100 mg, 0.59 mmol), ammonium acetate (182 mg,

2.36 mmol), 2,2,2-trifluoroethanol (1 mL), tere-butyl isocyanide (132 µl, 1.18 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were extracted with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate 5: 1 to 1: 2) to provide 85 mg of a mixture of diastereoisomers, [(1S, 3S, 4R) isomer / (1R, 3S , 4R) = 9: 1] as a white foam and

88 mg of a mixture of diastereoisomers, [(1S, 3S, 4R) isomer / (1R, 3S, 4R) isomer = 1: 9] as a white solid. Overall performance: 94%

Isomer rae- (1S, 3S, 4R):

ESI + MS: m / z = 334.1 (M + Na) +, 312.1 (M + 1) +; ESI-MS: m / z = 310.1 (M-1) -.

1H NMR (700 MHz, chloroform-d) 56.88 (s, 1H), 6.04 (s, 1H), 5.68 (ddd, J = 17.1, 10.1, 8.3 Hz, 1H ), 5.17 -5.06 (m, 2H), 4.48 (dd, J = 13.0, 4.5 Hz, 1H), 4.41 (dd, J = 13.0, 8.9 Hz, 1H), 2.71 (dd, J = 13.5, 7.5 Hz, 1H), 2.69-2.62 (m, 1H), 2.46 (td, J = 13.9, 8.7 Hz, 2H), 2.22 (dd, J = 14.1.8.6 Hz, 1H), 2.05 (s, 3H), 1.89 (dd, J = 13.5, 10 , 9Hz, 1H), 1.36 (d, J = 2.1Hz, 9H).

Isomer rae- (1R, 3S, 4R):

ESI + MS: m / z = 334.1 (M + Na) +, 312.1 (M + 1) +; ESI-MS: m / z = 310.1 (M-1) -.

1H NMR (700 MHz, chloroform-d) 56.80 (s, 1H), 5.89 (s, 1H), 5.71 (ddd, J = 17.1, 10.1, 8.3 Hz, 1H ), 5.19 -5.08 (m, 2H), 4.50 (dd, J = 12.4, 4.5 Hz, 1H), 4.36 (dd, J = 12.4, 7.6 Hz, 1H), 2.81 (dd, J = 14.1.8.6 Hz, 1H), 2.61-2.47 (m, 2H), 2.29 (d, J = 9.5 Hz , 2H), 2.05 (s, 3H), 1.98 (dd, J = 14.1, 9.2 Hz, 1H), 1.36 (s, 9H).

Step D. rae- (1S, 3S, 4S) -1-Acetamido-N- (tere-butyl) -3- (nitromethyl) -4- (2- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide.

A mixture of dppe (6.2 mg, 0.016 mmol), bis (1,5-cyclooctadiene) diiridium (I) dichloride (5.2 mg, 0.008 mmol) was dissolved in degassed dichloromethane (2 mL) under Ar. Separately, a solution of rae- (1S, 3S, 4r ) 1-acetamido-N- (tert-butyl) -3- (nitromethyl) -4-vinylcyclopentane-1-carboxamide (80 mg, 0.26 mmol, dr = 9: 1) in degassed dichloromethane (2 mL) and pinacolborane (55 µl, 0.38 mmol) was added dropwise. This solution was then added dropwise to the above-mentioned mixture of bis (1,5-cyclooctadiene) diiridium (I) dichloride and dppe in dichloromethane. The reaction mixture was stirred at rt overnight. The crude product was purified by silica gel flash chromatography (hexane / ethyl acetate 5: 1 to 1: 1) to provide 64 mg (56%) of the product as a colorless film (rac- (1S, 3S, 4S) - / rac- (1R3S, 4S) = 9: 1).

ESI + MS: m / z = 440.0 (M + 1) +; ESI-MS: m / z = 438.1 (M-1) -.

1H NMR (700 MHz, chloroform-d, rac- (1S, 3S, 4S) isomer 57.03 (s, 1H), 6.02 (s, 1H), 4.51 (dd, J = 12.8, 4.6 Hz, 1H), 4.45 (dd, J = 12.8, 9.2 Hz, 1H), 2.69 (dd, J = 13.2, 7.4 Hz, 1H), 2, 62-2.50 (m, 1H), 2.45 (dd, J = 13.8, 8.3 Hz, 1H), 2.18

(dd, J = 13.9, 8.6 Hz, 1H), 2.03 (s, 3H), 1.80-1.72 (m, 1H), 1.69 (dd, J = 13.1 , 9.8 Hz, 2H), 1.45-1.38 (m, 1H), 1.34 (s, 9H), 1.27 (s, 12H), 0.87-0.74 (m, 2H).

Step E. Rac- (2 - ((1S, 2S, 4S) -4-Acetamido-2 - (((tert-butoxycarbonyl) amino) methyl) -4- (tert-butoxycarbamoyl) cyclopentyl) ethyl) boronic acid.

To the solution of rac- (1S, 3S, 4S) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -4- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide (60 mg, 0.14 mmol; dr = 9: 1) and nickel chloride hexahydrate (32 mg, 0.14 mmol) in methanol ( 1 mL) was added portionwise sodium borohydride (52 mg, 1.37 mmol) at -10 ° C. The mixture was stirred at that temperature for 15 min. The reaction mixture was then quenched with water (1 mL). The aqueous layer was washed with ethyl acetate (2 x 1 mL). The aqueous layer was diluted with tetrahydrofuran (0.5 mL) and sodium bicarbonate (12 mg, 0.14 mmol) was added followed by di-tert-butyl dicarbonate (61 mg, 0.28 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). It was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 40 mg. (68%) of a desired product as a white solid (mixture of diastereoisomers 9: 1, isomer (2 - ((1S, 2S, 4S) as major diastereoisomer). ESI + MS: m / z = 450.1 (M + Na) +, 428.0 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 55.06 5.03 (m, 1H), 4.97-4.93 (m, 1H), 3.33-3.19 (m, 1H), 2.67-2.64 (m, 1H), 2.60-2.57 (m, 1H), 2.38-2.36 (m, 1H ), 2.19-2.12 (m, 1H), 2.02 (s, 3H), 1.89-1.87 (m, 1H), 1.78-1.75 (m, 1H), 1.72-1.69 (m, 1H), 1.46 (s, 9H), 1.35 (s, 9H), 0.89-0.80 (m, 2H).

Step F. Rac- (1S, 3S, 4S) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid dihydrochloride. Rac- (2 - ((1 S, 2S, 4S) -4-acetamido-2 - (((tert-butoxycarbonyl) amino) methyl) -4- (tert-butoxycarbamoyl) cyclopentyl) ethyl) boronic acid (40 mg, 0.09 mmol; dr = 9: 1) in 4 M HCl in dioxane (0.5 mL) and treated with 6 M HCl (aq) (2 mL). The reaction mixture was refluxed for 5h. Then the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (0.1-1% MeCN) to provide 3.7 mg (13%) of the 3: 1 diastereoisomer mixture, [major diastereoisomer is (1S, 3S, 4S)] like a colorless film. ESI + MS: m / z = 231.0 (M + 1) +, 213.9 (M-18) +. 1H NMR (700 MHz, deuterium oxide, (1S, 3S, 4S) isomer) 53.37-3.16 (m, 1H), 3.05-2.88 (m, 1H), 2.64-2 , 55 (m, 1H), 2.29 (dd, J = 13.8, 7.7 Hz, 1H), 2.24-2.10 (m, 2H), 1.99-1.90 (m , 1H), 1.76-1.69 (m, 1H), 1.61 (dd, J = 13.8, 11.4 Hz, 1H), 1.32-1.25 (m, 1H), 0.85-0.76 (m, 1H), 0.75-0.66 (m, 1H). Comparative Example 7. Rac- (1R, 3S, 4S) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid dihydrochloride

Step A. rac- (1R, 3S, 4S) -1-Acetamido-N- (tert-butyl) -3- (nitromethyl) -4- (2- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide.

A mixture of dppe (6.4 mg, 0.016 mmol), bis (1,5-cidooctadiene) diiridium (I) dichloride (5.4 mg, 0.008 mmol) was dissolved in degassed dichloromethane (2 mL), under Ar. Separately, a solution of rac- (1R, 3S, 4R) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -4-vinylcyclopentane-1-carboxamide (85 mg, 0.27 mmol ; dr = 9: 1) in degassed dichloromethane (2 mL) and a pinacolborane (59 µl, 0.41 mmol) was added dropwise. Then, the prepared solution was added dropwise to the above-mentioned mixture of bis (1,5-cyclooctadiene) diiridium (I) dichloride and dppe in dichloromethane. The reaction mixture was stirred at rt overnight. The crude product was purified by silica gel flash chromatography. (hexane / ethyl acetate 5: 1 to 1: 1) to provide 85 mg (71%) of the desired product as a colorless oil [9: 1 mixture of diastereoisomers, the major diastereoisomer is (1R, 3S, 4S)].

ESI + MS: m / z = 440.0 (M + 1) +; ESI-MS: m / z = 438.1 (M-1) -. 1H NMR (700 MHz, chloroform-d) 56.89 (s, 1H), 5.83 (s, 1H), 4.55 (dd, J = 12.1.4.6 Hz, 1H), 4, 35 (dd, J = 12.2, 8.2 Hz, 1H), 2.75 (dd, J = 14.2, 9.1 Hz, 1H), 2.42 (ddq, J = 12.9, 8.7, 4.3 Hz, 1H), 2.32 (dd, J = 13.3, 7.5 Hz, 1H), 2.06-2.03 (m, 1H), 2.02 (s , 3H), 1.99 (ddd, J = 14.2, 8.2, 1.0 Hz, 1H), 1.94-1.85 (m, 1H), 1.74-1.66 (m , 1H), 1.47-1.38 (m, 1H), 1.34 (s, 9H), 1.26 (s, 12H), 0.85 (ddd, J = 15.6, 9.9 , 5.6 Hz, 1H), 0.76 (ddd, J = 16.1, 9.9, 6.9 Hz, 1H).

Step B. Rac- (2 - ((1S, 2S, 4R) -4-acetamido-2 - (((tert-butoxycarbonyl) amino) methyl) -4- (tert-butoxycarbamoyl) cyclopentyl) ethyl) boronic acid.

To the solution of rac- (1R, 3S, 4S) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -4- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) cyclopentane-1-carboxamide (80 mg, 0.18 mmol; dr = 9: 1) and nickel chloride hexahydrate (43 mg, 0.18 mmol) in methanol ( 1 mL) was added portionwise sodium borohydride (69 mg, 1.82 mmol) at -10 ° C. The mixture was stirred at that temperature for 15 min. The reaction was then quenched with water (1 mL). The aqueous layer was washed with ethyl acetate. The aqueous layer was diluted with tetrahydrofuran (0.5 mL) and sodium bicarbonate (15 mg, 0.18 mmol) was added followed by di-tert-butyl dicarbonate (80 mg, 0.37 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 78 mg. (100%) as a white solid (9: 1 mixture of diastereoisomers; (1S, 2S, 4R isomer) is a major diastereoisomer). ESI + MS: m / z = 450.0 (M + Na) +, 428.0 (M + 1) +; ESI-MS: m / z = 426.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 54.86-4.79 (m, 2H), 3.32 3.28 (m, 1H), 3.10-3.03 (m, 1H), 2.74-2.71 (m, 1H), 2.45-2.32 (m, 2H), 2.06 (s, 3H) , 1.88-1.83 (m, 1H), 1.77-1.66 (m, 2H), 1.48 (s, 9H), 1.34 (s, 9H), 0.87-0 , 84 (m, 2H).

Step C. Rac- (1R, 3S, 4S) -1-amino-3- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid dihydrochloride.

Rac- (2 - ((1S, 2S, 4R) -4-acetamido-2 - (((tert-butoxycarbonyl) amino) methyl) -4- (tert-butoxycarbamoyl) cyclopentyl) ethyl) boronic acid (78 mg, 0.18 mmol; dr = 9: 1) in 4 M HCl in dioxane (1 mL) and treated with HCl

6 M (aq) (2 mL). The reaction mixture was refluxed for 5 h. Then the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (0.1-2% MeCN) to provide 16 mg (25%) as a colorless film (9: 1 diastereoisomer mixture, the (1S, 2S, 4R) isomer is a diastereoisomer principal).

ESI + MS: m / z = 231.0 (M + 1) +, 213.9 (M-18) +. 1H NMR (700 MHz, deuterium oxide) 53.28 (dd, J = 13.0, 3.7 Hz, 1H), 2.88 (dd, J = 12.9, 10.5 Hz, 1H), 2.66 (dd, J = 13.8, 7.4 Hz, 1H), 2.26 (dd, J = 14.6, 7.8 Hz, 1H), 2.24-2.12 (m, 1H), 2.06 (dd, J = 14.6, 11.3 Hz, 1H), 1.94-1.82 (m, 1H), 1.76-1.70 (m, 1H), 1 .68 (dd, J = 13.8, 11.2 Hz, 1H), 1.36-1.26 (m, 1H), 0.80 (ddd, J = 15.8, 10.5, 5, 5Hz, 1H), 0.75-0.63 (m, 1H).

Comparative Example 8. 3-Amino-1-benzyl-5- (2-boronoethyl) pyrrolidine-3-carboxylic acid dihydrochloride

Step A. 1-Benzyl-5-vinylpyrrolidin-3-one.

To a vigorously stirred solution of oxalyl chloride (0.79 mL, 9.2 mmol) in anhydrous dichloromethane (17 mL) was added dropwise a solution of dry DMSO (1.4 mL, 20 mmol) in dichloromethane (1 mL) at -78 ° C under argon. After stirring at that temperature for 70 min, a solution of 1-benzyl-5-vinylpyrrolidin-3-ol (1.5g, 7.7mmol, prepared according to: Katritzky et al. J. Org. Chem. 1999, 64, 6066) in dichloromethane (10 mL) with vigorous stirring, while keeping the temperature of the reaction mixture below -70 ° C. Stirring was continued for 30 min. Then, trimethylamine (5.3 mL, 38.3 mmol) was added. After stirring for 10 min, the reaction mixture was warmed to room temperature and diluted with DCM (100 mL), washed with saturated ammonium chloride (3 x 100 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography, on silica gel (hexane / AcOEt 20: 1 to 10: 1) to provide the desired product (0.6g, 39%) as a yellow oil. ESI + MS: m / z = 202.0 (M + 1) +. 1H NMR (700 MHz, chloroform-cf) 57.33 (dq, J = 17.3, 10.3, 8.9 Hz, 5H), 5.89 (dt, J = 17.8, 9.2 Hz , 1H), 5.43 -5.26 (m, 2H), 4.21 (d, J = 13.2 Hz, 1H), 3.38 (q, J = 8.4 Hz, 1H), 3 , 34-3.20 (m, 2H), 2.67 (d, J = 17.4Hz, 1H), 2.55 (dd, J = 18.1.6.3Hz, 1H), 2, 41-2.28 (m, 1H).

Step B. 3-Acetamido-1-benzyl-N- (tert-butyl) -5-vinylpyrrolidine-3-carboxamide.

To a mixture of 1-benzyl-5-vinylpyrrolidin-3-one (0.58 g, 2.9 mmol), ammonium acetate (0.9g, 11.5 mmol) and 2,2,2-trifluoroethanol (0 , 79 mL) tere-butyl isocyanide (0/65 mL, 5.8 mmol) was added dropwise at RT, and the mixture was stirred overnight. The reaction mixture was then quenched with water (80 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were washed with brine (80 mL), dried over MgSO4, and concentrated. The crude product was purified by flash chromatography, on silica gel (hexane / AcOEt 5: 1 to 2: 1) to provide 3-acetamido-1-benzyl-N- (tere-butyl) -5-vinylpyrrolidine-3-carboxamide (0.4 g, 40%) as a yellow oil.

ESI + MS: m / z = 344.7 (M + 1) +. ESI-MS: m / z = 342.2 (M-1) -. 1H NMR (700MHz, chloroform-d) 57.35-7.30 (m, 2H), 7.28-7.25 (m, 3H), 5.81-5.65 (m, 1H), 5 , 43 -5.21 (m, 2H), 4.17-4.12 (m, 1H), 3.61 (q, J = 8.4 Hz, 1H), 3.19-3.09 (m , 2H), 2.84 (dd, J = 13.6, 8.5 Hz, 1H), 2.64 (d, J = 9.2 Hz, 1H), 1.98 (s, 3H), 1 , 88 (dd, J = 13.6, 8.4 Hz, 1H), 1.30 (s, 9H).

Step C. 3-Acetamido-1-benzyl-N- (tere-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) pyrrolidine -3-carboxamide.

A mixture of dppe (27 mg, 0.068 mmol), bis (1,5-cyclooctadiene) diiridium (I) dichloride (23 mg, 0.034 mmol) was dissolved in dichloromethane (4 mL) and purged with argon. Separately, a solution of 3-acetamido-1-benzyl-N- (tere-butyl) -5-vinylpyrrolidine-3-carboxamide was dissolved in the same solvent (4 mL) (argon purged) and pinacolborane was added dropwise (215 µl, 1.48 mmol). Then, the solution of 3-acetamido-1-benzyl-N- (tere-butyl) -5-vinylpyrrolidine-3-carboxamide and pinacolborane in DCM was added dropwise to the above-mentioned mixture of bis (1,5 -cyclooctadiene) diiridium (I) and dppe in DCM at RT. The reaction mixture was stirred at room temperature overnight. After that time, the crude product was purified by column chromatography, on silica gel (hexane / AcOEt 5: 1 to 2: 1) to provide the desired product (260 mg, 48%) as a yellow oil. ESI + MS: m / z = 472.9 (M + 1) +, 372.0 (M-Pin-H2O + 1) +, ESI-MS: m / z = 388.1 (M-Pin-1) -.1H NMR (700 MHz, chloroform- d) 57.35 - 7.29 (m, 3H), 7.27 (dd, J = 7.4, 1.1 Hz, 2H), 4.22 (d , J = 12.4 Hz, 1H), 3.16-3.10 (m, 2H), 2.73 (dd, J = 13.4, 8.3 Hz, 1H), 2.58 (d, J = 9.1 Hz, 1H), 1.96 (s, 3H), 1.78 (dd, J = 13.4, 8.4 Hz, 1H), 1.30 (s, 9H), 1, 29 (t, J = 3.7Hz, 17H).

Step D. 3-Amino-1-benzyl-5- (2-boronoethyl) pyrrolidine-3-carboxylic acid dihydrochloride.

A mixture of 3-acetamido-1-benzyl-N- (tere-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) pyrrolidine -3-carboxamide (140 mg, 0.3 mmol) and HClac 6N (3 mL) were heated under reflux for 6h. Then a solvent was evaporated and 6N HClac (2.5 ml) was added to the residue and the mixture was stirred at 90 ° C overnight. Then an additional amount of concentrated HCl (0.5 ml) was added and stirred at 90 ° C for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.1-2% MeCN in water) to provide the desired product (11 mg, 12%, single diastereomer) as a colorless film. ESI + MS: m / z = 293.0 (M + 1) +, 274.9 (M-H2O + 1) +, 247.0 (M-2xH2O + 1) +, ESI-MS: m / z = 291.0 (M-18-1) -, 273.1 (M-H2O-1) -. 1H NMR (700 MHz, deuterium oxide) 57.49 (d, J = 3.5 Hz, 5H), 4.31 (d, J = 13.1 Hz, 1H), 3.93 (d, J = 13.0 Hz, 1H), 3.78 (s, 1H), 3.49 (d, J = 13.0 Hz, 1H), 2.77-2.64 (m, 1H), 2.48 ( s, 1H), 2.20 (d, J = 28.6 Hz, 1H), 1.81 (s, 1H), 0.82 (ddd, J = 31.8, 10.3, 5.5 Hz , 2H).

Comparative Example 9. 3-amino-5- (2-boronoethyl) pyrrolidine-3-carboxylic acid dihydrodoride

Step A. 3-Acetamido-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) -pyrrolidin-3- carboxamide.

The mixture of 3-acetamido-1-benzyl-N- (fe / 'c-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Ethyl) pyrrolidine-3-carboxamide (0.1g, 0.21mmol, Comparative Example 8, Step C), palladium on activated carbon (10mg) and methanol (3mL) was stirred under a hydrogen atmosphere overnight. Then a drop of HClac (2M) was added and the hydrogenolysis was continued for 12 days. The reaction mixture was filtered with celite and washed with MeOH. The filtrate was concentrated to provide the desired product (83 mg, approx. 100%) as a yellow oil. ESI + MS: m / z = 382.1 (M + 1) +, 282.1 (M-Pin-18 + 1) +, ESI-MS: m / z = 380.1 (M-1) -, 280.0 (M-Pin-18-1) -. 1H NMR (700 MHz, chloroformod) 53.74

(d, J = 11.1 Hz, 1H), 2.73 (dd, J = 13.5, 7.1 Hz, 1H), 2.09 (s, 3H), 1.82 (q, J = 7.2 Hz, 2H), 1.36 (s, 9H), 1.27 (s, 15H), 0.98-0.86 (m, 2H).

Step B. 3-Amino-5- (2-boronoethyl) pyrrolidine-3-carboxylic acid dihydrochloride.

A mixture of 3-acetamido-N- (fe / 'c-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) pyrrolidin- 3-carboxamide (74 mg, 0.19 mmol) and 6N HClac (2.5 mL) were stirred at 90 ° C for 2 days. Then an additional amount of concentrated HCl (0.5 ml) was added and it was stirred at 90 ° C for 1 day. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.1-0.1% MeCN in water) to provide the desired product (13 mg, 29%, single diastereoisomer) as a colorless film. . ESI + m S: m / z = 203.1 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 54.04 (d, J = 13.4 Hz, 1H), 3.87 (d, J = 7.3 Hz, 1H), 3.55 (d, J = 13.4 Hz, 1H), 3.06-292 (m, 1H), 2.65

(d, J = 23.1 Hz, 1H), 2.44-2.35 (m, 1H), 1.86 (ddd, J = 31.5, 14.9, 7.7 Hz, 1H), 1.00-0.94 (m, 1H), 0.84 (t, J = 8.3 Hz, 1H).

Comparative Example 10. Rae- (1S, 3R) -1-amino-3- (2-boronoethyl) cidohexane-1-carboxylic acid hydrodoride

Step A. 1-Acetamido-N- (tere-butyl) -3-vinylcyclohexanecarboxamide.

To the stirred solution of 3-vinylcyclohexanone (2.50 g, 20 mmol, 1 equiv.) (Prepared from cyclohex-2-enone using a method from the literature. Tetrahedmn, 67, (2011), 4192-4195) and ammonium acetate (6.20 g, 80 mmol, 4 equiv.) in 2,2,2-trifluoroethanol (3 mL), tere-butyl isocyanide (3.32 g, 4.5 mL, 40 mmol) was added , 2 equiv.) Via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (using EtOAc-hexane, 1:10 as the eluent) to provide 1-acetamido-N- (tere-butyl) -3-vinylcyclohexanecarboxamide as a mixture of diastereoisomers dr = 1: 1 (2.62g, 49%, light yellow oil). ESI + MS: m / z = 289.2 (M + Na) +, ESI-MS: m / z = 265.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 55.74 ( dddd, J = 17.1, 12.7, 10.5, 6.3 Hz, 1H), 5.01 (dq, J = 17.3, 1.6 Hz, 1H), 4.94 (ddt, J = 10.5, 4.0, 1.4 Hz, 1H), 2.61 (m, 1H), 2.28 (m, 1H), [2.05, 1.95 (2s, 3H, two diastereoisomers)], 1.76-1.67 (m, 2H), 1.62 (td, J = 13.9, 3.9 Hz, 1H), 1.55-1.48 (m, 1H), [1.33, 1.31 (2s, 9H, two diastereoisomers)], 1.18-1.11 (m, 1H), 1.09 (dq, J = 12.1.4.3 Hz, 1H) .

Step B. 1-Acetamido-N- (tere-butyl) -3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) -cyclohexanecarboxamide.

A round bottom flask filled with bis (1,5-cyclooctadiene) diiridium (I) dichloride (144 mg, 0.21 mmol, 0.03 equiv.), 1,2-bis (diphenylphosphino) ethane (170 mg, 0.42 mmol, 0.06 equiv.) And dry CH2Cl2 (15 mL) was purged with argon (sparging). Subsequently, the separately prepared solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.82 g, 2.10 mL,

14.2 mmol, 2 equiv.), 1-acetamido-N- (tere-butyl) -3-vinylcyclohexanecarboxamide (1.90 g, 7.10 mmol, 1 equiv.) In 20 mL of dry CH2Cl2 was added successively to room temperature. The resulting light yellow mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was subjected directly to silica gel flash chromatography (using AcOEt-Hexane, 1:10 as the eluent) to provide the 1-acetamido-N- (tere-butyl) -3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) -cyclohexane target as a mixture of diastereoisomers dr = 1: 1 (1.68, 60%, oil sticky light yellow). ESI + MS: m / z = 395.1 (M + H) +, ESI-MS: m / z = 393.1 (M-1) -. 1H NMR (700 MHz, chloroform-d) 52.62 (dd, J = 45.4, 12.8 Hz, 2H), 2.25 (dd, J = 60.2 , 12.3 Hz, 2H), [2.01, 1.93 (2s, 3H, two diastereoisomers)] 1.74 (d, J = 12.9 Hz, 2H), 1.67 (ddt, J = 14.4, 7.7, 3.4 Hz, 2H), 1.58 (td, J = 13.8, 4.0 Hz, 1H), [1.31, 1.30 (2s, 9H, two diastereoisomers)], [1.23, 1.24 (2s, 12H, two diastereoisomers)], 0.86-0.71 (m, 4H).

Step C. Rac- (1S, 3R) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid hydrochloride.

A mixture of 1-acetamido-N- (fe / 'c-butyl) -3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) -cyclohexanecarboxamide

(250 mg, 0.63 mmol) and 25 mL of 6N HCl was refluxed for 6 hours. After concentrating, the residue was subjected to preparative HPLC chromatography (gradient elution 0.1-2%, acetonitrile-water). Overall yield of isolated stereoisomers of the target product (44 mg, 28%). Rac- (1S, 3R) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid hydrochloride diastereoisomerically pure (6.1 mg, 4%, white solid) ESI + MS: m / z = 216.1 (M + H) + ESI-MS: m / z = 214.1 (M-1) - 1H NMR (700 MHz, D2O) 52.25 - 2.16 (m, 2H), 1 , 80-1.72 (m, 2H), 1.60 (dddd, J = 22.2, 16.0, 8.4, 3.5 Hz, 2H), 1.48 (td, J = 13, 2, 4.5 Hz, 1H), 1.31 (m, 2H), 1.16 (t, J = 12.6 Hz, 1H), 0.82 (td, J = 12.7, 12.2 , 3.7 Hz, 1H), 0.75 (t, J = 7.7 Hz, 2H).

Comparative Example 11. Rac- (1R, 3R) -1-amino-3- (2-boronoethyl) cyclohexane-1-carboxylic acid hydrochloride

Isolated by preparative HPLC (elution gradient 0.1-2%, acetonitrile-water) after step C of Comparative Example 10. Yield: 8.8 mg, 5.0%, white solid. ESI + MS: m / z = 216.1 (M + H) +, ESI-MS: m / z = 214.1 (M-1) -

1H NMR (700MHz, D2O) 1.97-1.86 (m, 2H), 1.83-1.77 (m, 2H), 1.61 (dd, J = 14.4, 12.8 Hz, 1H), 1.45-1.25 (m, 5H), 1.00-0.91 (m, 1H), 0.72 (t, J = 8.1 Hz, 2H).

Comparative Example 12. 1-Amino-3- (2-boronoethyl) cycloheptane-1-carboxylic acid hydrochloride

Step A. 3-Vinylcycloheptan-l-one.

Vinylmagnesium bromide (1M in THF) (18.2 mL, 18.2 mmol) and HMPA (6.31 mL, 36.3 mmol) were added separately dropwise to a suspension of CuBr x Me2S (281 mg, 1 , 36 mmol) in dry THF (70 mL) at -78 ° C under argon for 10 min. After stirring at -78 ° C for 15 min, a solution of cyclohept-2-en-1-one (1g,

9.1 mmol) and TMSCl (5.77 ml, 45.5 mmol) in dry THF (20 mL) for 30 min. The reaction mixture was stirred at

-78 ° C for 2h. The mixture was then quenched with saturated NH4Cl (130 mL) and washed with AcOEt (3 x 100 mL). The organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (DCM) to provide 3-vinylcycloheptan-1-one (1.3 g, 100%) as a yellow liquid. 1H NMR (700 MHz, chloroform-d) 55.81 (ddd, J = 17.2, 10.4, 6.8 Hz, 1H), 5.06-4.94 (m, 2H), 2.58 - 2.56 (m, 2H), 2.54-2.50 (m, 2H), 2.44-2.38 (m, 1H), 2.01-1.86 (m, 3H), 1 , 69-1.58 (m, 1H), 1.51-1.41 (m, 2H).

Step B. 1-Acetamido-N- (te / 'c-butyl) -3-vinylcycloheptane-1-carboxamide.

To a mixture of 3-vinylcycloheptan-1-one (1.2 g, 9.19 mmol), ammonium acetate (2.8 g, 36.8 mmol),

2,2,2-trifluoroethanol (2.5 mL) was added te / r-butyl isocyanide (2.1 mL, 18.4 mmol) dropwise and the mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. (AcOEt / hexane, 1: 5). The reaction mixture was quenched with water (70 mL) and washed with ethyl acetate (3 x 70 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by flash chromatography, on silica gel hexane / AcOEt (2: 1 to 1: 1) (a mixture of 3: 1 and 1: 2 diastereoisomers and a single diastereoisomer was isolated). ESI + MS: m / z = 303.1 (M + Na) +, ESI-MS: m / z = 279.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) mixture of diastereoisomers ( 3: 1) 5.88 -5.76 (m, 1H), 5.05-4.85 (m, 2H), 2.34-2.27 (m, 1H), 2.23-2, 16 (m, 1H), 2.07 (s, 2H, CHa (1 day)), 2.01 (s, 1H, CHa (2 day)), 1.95 (dd, J = 14.9, 10 , 5 Hz, 1H), 1.89 (dd, J = 14.6, 6.3 Hz, 1H), 1.80 (td, J = 12.6, 6.8 Hz, 2H), 1.68 - 1.57 (m, 3H), 1.56-1.47 (m, 1H), 1.44 (ddd, J = 18.9, 10.3, 5.1 Hz, 1H), 1.35 (s, 2H, t-Bu (2 day)), 1.34 (s, 7H t-Bu (1 day)). 1H NMR (700 MHz, chloroform-d, single diastereoisomer) 55.85 (ddd, J = 17.4, 10.4, 7.1 Hz, 1H), 5.05-4.85 (m, 2H), 2.62 (d, J = 14.3 Hz, 1H), 2.43-2.34 (m, 1H), 2.23-2.09 (m, 2H), 2.01 (s, 3H) , 1.90-1.82 (m, 2H), 1.74 (dd, J = 13.0, 6.8 Hz, 1H), 1.57

(dd, J = 14.4, 9.1 Hz, 1H), 1.52-1.43 (m, 2H), 1.35 (s, 9H), 1.33-1.25 (m, 1H ).

Step C. 1-Acetamido-N- (te / 'c-butyl) -3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) -cycloheptane -1- carboxamide.

A mixture of dppe (30 mg, 0.075 mmol), bis (1,5-cyclooctadiene) diiridium (I) dichloride (25 mg, 0.037 mmol) was dissolved in dichloromethane (4.5 mL) and purged with argon. Separately, a solution of 1-acetamido-N- (te / 'c-butyl) -3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was dissolved ethyl) cycloheptane-1-carboxamide (dr = 3: 1) in the same solvent (4.5 mL) (purged with argon) and a pinacolborane (235 µl, 1.62 mmol) was added dropwise. Then, this solution was added dropwise to the above-mentioned mixture of bis (1,5-cyclooctadiene) diiridium (I) dichloride and dppe in DCM at RT. The reaction mixture was stirred at room temperature overnight. After that time, the crude product was purified by flash chromatography, on silica gel (hexane / AcOEt 2: 1 to 1: 1) to provide the desired product (0.53g, 100%, dr = 3: 1) as a yellow oil. ESI + MS: m / z = 431.1 (M + Na) +, 409.2 (M + 1) +, ESI-MS: m / z = 407.3 (M-1) -. 1H NMR (700 MHz, chloroform-d) 52.07 (s, 1H CH3 (2 day)), 2.05 (s, 2H CH3 (1 day)), 1.85-1.74 (m, 3H), 1.59 (dq, J = 11.4, 5.8 Hz, 3H), 1.45-1.37 (m, 3H), 1.35 (s, 3H t-Bu (2 day)), 1.34 ( s, 6H t-Bu (1 day)), 1.30 (s, 5H), 1.27 (d, J = 3.0 Hz, 11H), 0.86-0.73 (m, 2H).

E cap D. H id roc lo ru ro del acid 1 -am in o -3 - (2 -bo ro noe til) c ic lo hep ta no -1 -ca rb oxylic.

A mixture of 1-acetamido-N- (tert-butyl) -3- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cycloheptane-1-carboxamide (200 mg, 0.49 mmol, dr = 3: 1) and 6N HClac (2 mL) was refluxed for 4h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.1-7% MeCN in water) to provide the desired product (49 mg, 38%, dr = 3: 1) as a solid White. ESI + MS: m / z = 230.0 (M + 1) +, 195.0 (M-2xH2O + 1) +, ESI-MS: m / z = 210.1 (M-18-1) -. 1H NMR (700 MHz, deuterium oxide) 52.31-2.24 (m, 0.7H (1 day)), 2.23-2.14 (m, 0.3H (2 day)), 2, 10 (dd, J = 15.6, 10.7 Hz, 1H), 1.88-1.72 (m, 3H), 1.71-1.54 (m, 3H), 1.53-1, 42 (m, 1H), 1.42-1.23 (m, 3H), 1.21-1.13 (m, 0.7H (1 day)), 1.13-1.04 (m, 0 , 3H (2 day)), 0.80-0.65 (m, 2H).

Example 13. Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride

General synthetic path for examples 13 and 14.

Step A. Rac- (1 R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate and rac- (1 R, 2S, 4R) -2-acetamido-2 acetate - (tert-butylcarbamoyl) -4-vinylcyclohexyl.

Prepared from ethyl rac- (1R, 4R) -4-ethenyl-2-oxocyclohexyl (Diederich, F. et al, Org Biomol Chem 2009, 7, 3947 3957), using the procedure described in Comparative Example 1 , step A. The crude product was purified by silica gel flash chromatography (hexane / ethyl acetate 4: 1 to 1: 1). Overall yield: 430 mg (60%).

Isolated: 150 mg (mixture of diastereoisomers A: B = 4: 1, white solid) and 280 mg (A: B = 3: 7, colorless semi-solid). A (rac- (1R, 2R, 4R) isomer): ESI + MS: m / z = 347.1 (M + Na) +. 1H NMR (700 MHz, CDCls) 57.97 (bs, 1H), 6.44 (bs, 1H), 5.75 (ddd, J = 17.0, 10.4, 6.3 Hz, 1H), 5.40 (d, J = 8.5 Hz, 1H), 5.05-4.98 (m, 2H), 3.55 (ddd, J = 13.2, 8.5, 4.8 Hz, 1H), 2.98 (dt, J = 13.5, 2.7 Hz, 1H), 2.10-2.05 (m, 4H), 2.04 (s, 3H), 2.04-1 , 95 (m, 3H), 1.86-1.82 (m, 1H), 1.37 (s, 9H).

B (rac- (1R, 2S, 4R) isomer): ESI + MS: m / z = 347.1 (M + Na) +. 1H NMR (700 MHz, CDCla) 56.93 (bs, 1H), 5.79 (bs, 1H), 5.73 (ddd, J = 17.0, 10.4, 6.3 Hz, 1H), 5.31 (dd, J = 12.1, 4.8 Hz, 1H), 5.05 - 4.97 (m, 2H), 3.12 (dt, J = 14.2, 2.9 Hz, 1H), 2.17 (s, 3H), 2.10-2.07 (m, 1H), 2.07 (s, 3H), 2.04-2.00 (m, 1H), 1.91 - 1.78 (m, 2H), 1.57-1.50 (m, 1H), 1.49-1.44 (m, 1H), 1.33 (s, 9H).

Step B. Rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) acetate -2-yl) ethyl) cydohexyl.

Prepared from rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate (140 mg, 0.43 mmol, dr = 4: 1), using the procedure described in Comparative Example 1, step B. The crude product was purified by flash chromatography on silica gel (hexane / ethyl acetate 4: 1 to 1: 1). Yield: 85 mg (44%). ESI + MS: m / z = 475.1 (M + Na) +. 1H NMR (700 MHz, CDCla) 57.89 (bs, 1H), 6.36 (bs, 1H), 5.26 (d, J = 8.8 Hz, 1H), 3.48 (ddd, J = 11.9, 8.9, 4.8 Hz, 1H), 2.97 (dt, J = 13.6, 2.6 Hz, 1H), 2.06-2.03 (m, 4H), 2 , 02 (s, 3H), 1.96-1.90 (m, 2H), 1.83-1.78 (m, 2H), 1.36 (s, 9H), 1.26 (s, 12H ), 0.96-0.87 (m, 2H), 0.82-0.74 (m, 2H).

Step C. Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride.

Prepared from (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate (70 mg, 0.155 mmol), using the procedure described in Comparative Example 1, step C. The crude product was purified by preparative HPLC (0.1-2% MeCN). Yield: 18 mg (43%). ESI + MS: m / z = 232.0 (M + H) +. 1H NMR (700 MHz, D2O) 53.74

(dd, J = 11.8, 5.3 Hz, 1H), 2.23-2.17 (m, 1H), 2.00 (ddd, J = 16.6, 13.2, 4.0 Hz , 1H), 1.91-1.83 (m, 2H), 1.82-1.75 (m, 1H), 1.30-1.24 (m, 3H), 0.98 (qd, J = 13.3, 3.7 Hz, 1H), 0.73 (dd, J = 9.2, 6.6 Hz, 2H).

Example 14. Rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride

Step A. Rac- (1R, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) acetate -2-yl) ethyl) cyclohexyl.

Prepared from rac- (1R, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate (255 mg, 0.56 mmol, dr = 7: 3, Example 13, step A) in the same manner as in Example 13, step B. The crude product was purified by flash chromatography on silica gel (hexane / ethyl acetate 4: 1 to 1: 1). Yield: 212 mg (60%) dr = 2: 1. ESI + MS: m / z = 453.1 (M + H) +, 475.1 (M + Na) +.

Major diastereoisomer (colorless oil): 1H NMR (700 MHz, CDCb) 57.02 (bs, 1H), 5.75 (bs, 1H), 5.30 (dd, J = 12.1.4.8 Hz, 1H), 3.11-3.04 (m, 1H), 2.13 (s, 3H), 2.05 (s, 3H), 2.04-2.01 (m, 1H), 1.84 - 1.77 (m, 2H), 1.49-1.43 (m, 1H), 1.32 (s, 9H), 1.25 (s, 12H), 1.24-1.16 (m , 2H), 1.14-1.00 (m, 1H), 0.93-0.87 (m, 2H), 0.79-0.72 (m, 1H). E cap B. H id roc lo ru ro del ác ido ra c - (1 S, 2 R, 5 R) -1 -am in o -5 - (2 -bo ro noe til) -2 -h id ro x ic ic lo hexane -1 -ca rb oxylic o.

Prepared from acetate of rac- (1R, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) ethyl) cidohexyl (120 mg, 0.155 mmol, dr = 2: 1) procedure described in Comparative Example 1, step C. The crude product was purified by preparative HPLC (0.1-1% MeCN ). Obtained: 35 mg (49%, single diastereoisomer). ESI + MS: m / z = 232.0 (M + H) +. 1H NMR (700 MHz, D2O) 54.19 (dd, J = 12.2, 5.2 Hz, 1H), 2.02 (dt, J = 14.9, 2.7 Hz, 1H), 2, 00-1.96 (m, 1H), 1.88-1.82 (m, 1H), 1.66 (dd, J = 14.7, 12.5 Hz, 1H), 1.46-1, 39 (m, 1H), 1.36-1.29 (m, 3H), 1.14-1.06 (m, 1H), 0.73 (t, J = 8.0 Hz, 2H).

Example 15. Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride

Step A. Rac- (1 S, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate and rac- (1 S, 2R, 4R) -2-acetamido-2 acetate - (tert-butylcarbamoyl) -4-vinylcyclohexyl.

Prepared from racemic (1S, 4R) -4-ethenyl-2-oxocyclohexyl acetate (Diederich, F. et al., Org. Biomol. Chem.

2009, 7, 3947-3957), using the procedure described in Comparative Example 1, step A. The crude product was purified by flash chromatography on silica gel (hexane / ethyl acetate 4: 1 to 1: 1). Yield: 516 mg (72%). Obtained: 90 mg (single diastereoisomer A, white solid), 266 mg (A: B = 2: 1, white solid) and 160 mg of the mixture of other diastereoisomers.

A (rac- (1S, 2S, 4R) isomer): ESI + MS: m / z = 347.1 (M + Na) +; ESI-MS: m / z = 323.2 (M-1) -.

1H NMR (700 MHz, CDCls) 57.34 (bs, 1H), 6.10 (bs, 1H), 5.82 (ddd, J = 17.0, 10.4, 6.2 Hz, 1H), 5.34 (bs, 1H), 5.11

(dt, J = 17.3, 1.4 Hz, 1H), 5.04 (dt, J = 10.4, 1.3 Hz, 1H), 2.23-2.14 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 2.00-1.96 (m, 1H), 1.92 (ddd, J = 14.9, 6.4, 3.6 Hz, 1H), 1.72-1.66 (m, 1H), 1.62-1.58 (m, 1H), 1.41-1.33 (m, 2H), 1.31 (s, 9H).

B (mixture of diastereoisomers, 2: 1): ESI + MS: m / z = 347.1 (M + Na) +; ESI-MS: m / z = 323.1 (M-1) -.

Step B. Rac- (1S, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) acetate -2-yl) ethyl) cyclohexyl.

Prepared from rac- (1S, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate (80 mg, 0.25 mmol), using the procedure described in Comparative Example 1 , step B. The crude product was purified by silica gel flash chromatography (hexane / ethyl acetate 3: 1 to 1: 1). Yield: 89 mg (79%), white solid. ESI + MS: m / z = 453.0 (M + H) +, 475.0 (M + Na) +; ESI-MS: m / z = 451.1 (M-1) -. 1H NMR (700 MHz, CDCls) 57.45 (bs, 1H), 6.11 (bs, 1H), 5.33 (bs, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 1.96-1.80 (m, 4H), 1.64-1.59 (m, 1H), 1.47 - 1.39 (m, 3H), 1.17-1.12 (m, 1H), 0.88-0.81 (m, 2H).

Step C. Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride.

Prepared from rac- (1S, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) ethyl) cyclohexyl (26 mg, 0.155 mmol) using the method described in Comparative Example 1, step C. The crude product was purified by preparative HPLC (0.1-1% MeCN). Yield: 11 mg (72%). Colorless film. ESI + MS: m / z = 214.0 (M-18 + H) +, 232.0 (M + H) +. 1H NMR (700MHz, D2O) 53.96 (s, 1H), 1.88-1.83 (m, 2H), 1.79-1.74 (m, 1H), 1.71-1.64 (m, 1H), 1.62-1.56 (m, 1H), 1.39-1.33 (m, 3H), 1.30-1.22 (m, 1H), 0.76 (t , J = 8.1 Hz, 2H).

Example 16. Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride

Step A. Rac- (1S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) acetate -yl) ethyl) cyclohexyl.

Prepared from the mixture of rac- (1S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl acetate diastereoisomers (dr = 2: 1) (255 mg, 0.79 mmol, Example 15, step A), using the procedure described in Example 15, step B. The crude product was purified by flash chromatography on silica gel (hexane / ethyl acetate 4: 1 to 2: 1). Yield: 100 mg of rac- (1S, 2S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) ethyl) cyclohexyl and 150 mg of the rac- (1S, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5) acetate mixture , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl and rac- (1S, 2S, 4R) -2-acetamido-2-tert-butylcarbamoyl) -4- (2- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl (1: 1). Yield: 70%, white solids. Rac- (1S, 2R, 4R) isomer: ESI + MS: m / z = 475.1 (M + Na) +; ESI-MS: m / z = 451.3 (M-1) -. 1 * 5

1H NMR (700 MHz, CDCls) 57.42 (bs, 1H), 6.01 (bs, 1H), 5.56 (bs, 1H), 2.70-2.62 (m, 1H), 2, 12 (s, 3H), 1.94 (s, 3H), 1.91-1.80 (m, 3H), 1.45-1.41 (m, 3H), 1.34 (s, 9H) , 1.27 (s, 12H), 1.19-1.12 (m, 2H), 0.81-0.73 (m, 2H).

Step B. Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride.

Prepared from rac- (1S, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) ethyl) cyclohexyl (150 mg, 0.33 mmol; dr = 1: 1), using the procedure described in Example 15, step C. The crude product was purified by preparative HPLC (0.1 - MeCN 1 %). Yield: 10 mg (11%, colorless film), dr = 2: 1; Rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride is a major diastereoisomer. ESI + MS: m / z = 214.0 (M-18 + H) +, 232.0 (M + H) +. 1H NMR (700MHz, D2O) 4.08-4.05 (m, 1H), 1.94-1.88 (m, 2H), 1.84-1.81 (m, 1H), 1, 76-1.70 (m, 1H), 1.64-1.59 (m, 1H), 1.45-1.30 (m, 3H), 1.28-1.21 (m, 1H), 0.76 (t, J = 8.1 Hz, 2H).

E jem p lo 17. D ih id ro c lo ru ro de l ác ido ra c - (1 R, 2 S, 5 R) -1 -am in o -5 - (2 -bo ro noe til) -2 - ((d im e tila m in o) methyl) -c ic lo hexane -1 -ca rb oxylic

Step A. Ethyl 2-Oxocyclohex-3-en-1-carboxylate.

To a freshly distilled solution of diisopropylamine (58.3 mL, 0.416 mol, 2 equiv.) In dry THF (375 mL) was added dropwise a solution of n-BuLi (2.5 M in hexanes) (166.4 mL, 0.416 mole, 2 equiv.) at -78 ° C under argon. The reaction mixture was warmed to room temperature, stirred for 20 minutes, and cooled to -78 ° C. Then, the solution of 2-cyclohexen-1-one (20 g, 20.1 mL, 0.208 mol, 1 equiv.) In THF (78 mL) was added dropwise and the mixture was stirred for 1h at -78 ° C. Ethyl chloroformate (33.8 g, 29.7 mL, 0.312 mol, 1.5 equiv) was added dropwise and the resulting reaction mixture was stirred for 1h at -78 ° C, then allowed to warm to temperature. atmosphere and the agitation continued all night. The mixture was quenched with a saturated NH4Cl solution (250 mL) and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine and water, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 5: 1) to provide ethyl 2-oxocyclohex-3-en-1-carboxylate (18.5g, 53% ) as a yellow liquid. 1H NMR (700 MHz, chloroform-d) 56.96 - 6.90 (m, 1H), 5.98 (dt, J = 10.1.2.0 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.35-3.29 (m, 1H), 2.46-2.39 (m, 1H), 2.36-2.26 (m, 3H), 2.19-2 , 11 (m, 1H), 1.27-1.14 (m, 2H).

Step B. Ethyl 2-Hydroxy-4-vinylcyclohex-1-en-1-carboxylate.

A solution of vinylmagnesium bromide (1M in THF) (119 mL, 0.119 moles, 2 equiv.) And HMPA (41.6 mL) were added dropwise to a suspension of CuBr x Me2S (1.83 g, 8, 92 mmol, 0.15 equiv.) In dry THF (250 mL) at -78 ° C for 15 min under argon. After stirring at -78 ° C for 15 min, a solution of ethyl 2-oxocyclohex-3-en-1-carboxylate (10 g, 59.5 mmol, 1.0 equiv.) And TMSCl were added dropwise (37.7 mL, 0.297 mol, 5 equiv.) In dry THF (100 mL) (over 30 min). The reaction mixture was stirred at -78 ° C for 2h. The mixture was then quenched with saturated aqueous NH4Cl (200 mL) and washed with AcOEt (3 x 150 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (hexane / AcOEt 10: 1) to provide ethyl 2-hydroxy-4-vinylcyclohex-1-en-1-carboxylate (4.94 g, 42%) as a light yellow liquid. 1H NMR (700 MHz, chloroform-d) 55.91 -5.70 (m, 1H), 5.16-4.90 (m, 2H), 4.22 (qd, J = 7.1.0, 5Hz, 2H), 2.45-2.30 (m, 3H), 2.24-2.12 (m, 2H), 1.89-1.74 (m, 1H), 1.45-1 , 18 (m, 5H).

Step C. ethyl rac- (1R, 2R, 4R) -2-Acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate and rac- (1R, 2S, 4R) -2-acetamido-2 - Ethyl - (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate.

To the stirred solution of ethyl 2-hydroxy-4-vinylcyclohex-1-en-1-carboxylate (3.0 g, 15.29 mmol, 1 equiv.) And ammonium acetate (4.71g, 61.15 mmol , 4 equiv.) In 2,2,2-trifluoroethanol (3 mL), tert- butyl isocyanide was added dropwise

(3.44 mL, 30.58 mmol, 2 equiv.) Via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 2: 1) to provide the corresponding product as separable diastereoisomers (dr = 2: 1) (overall yield 2.42 g, 47%). ESI + MS: m / z = 339.1 (M + 1) +, 361.1 (M + Na) +. The minor diastereomer (rac- (1R, 2S, 4R) -2-acetamido-2- (FERC-butylcarbamoyl) -4-vinylcyclohexene-1-carboxylate): 0.90 g, (17%), white solid.

1H NMR (700 MHz, chloroform-d) 57.59 (s, 1H), 7.27 (s, 1H), 5.73 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H ), 5.07-4.91 (m, 2H), 4.26-4.09 (m, 2H), 3.23 (ddd, J = 13.8, 2.9, 1.7 Hz, 1H ), 2.80 (dd, J = 13.3, 3.6 Hz, 1H), 2.16-2.11 (m, 1H) 2.10 (s, 3H), 1.95 (dq, J = 13.4, 3.6 Hz, 1H), 1.72 (qd, J = 13.3, 3.9 Hz, 1H), 1.32-1.28 (m, 13H), 1.26 - 1.13 (m, 2H). The main diastereoisomer (ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate): 1.52 g (30%); white solid. 1H NMR (700 MHz, chloroform-d) 58.10 (s, 1H), 7.57 (s, 1H), 5.72 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H), 5.03 - 4.91 (m, 2H), 4.20 (ddq, J = 59.5, 10.8, 7.1 Hz, 2H), 3.29 (d, J = 13.8 Hz, 1H), 2.28 (dd, J = 12.4, 4.4 Hz, 1H), 2.14 (dq, J = 11.6, 4.2, 3.6 Hz, 1H), 2.11-2 , 02 (m, 2H), 1.99 (s, 3H), 1.85-1.80 (m, 1H), 1.33-1.30 (m, 13H), 1.10 (qd, J = 13.2, 4.4 Hz, 1H).

Step D. rac- (1 R, 2R, 5R) -1-Acetamido-N- (tert-butyl) -2-formyl-5-vinylcyclohexane-1-carboxamide.

To a solution of ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (0.5 g,

1.48 mmol) in dry dichloromethane (15 mL) a solution of DIBAL-H (1M in DCM; 4.6 mL, 4.58 mmol) was added dropwise at -78 ° C under argon. The reaction mixture was stirred at -78 ° C and monitored by TLC. After 1 hr, the reaction mixture was quenched with methanol. A sticky white precipitate was filtered through the celite pad and washed with dichloromethane. The resulting filtrate was concentrated in vacuo to provide the crude product as a colorless oil.

(0.43 g 99%). The crude product was used in the next step without further purification. ESI + MS: m / z = 317.1 (M + Na) +.

1H NMR (700MHz, chloroform-d) 59.78 (s, 1H), 5.79 -5.74 (m, 1H), 5.06-4.98 (m, 1H), 3.30-3 , 25 (m, 1H), 2.25-2.17 (m, 1H), 2.11-2.07 (m, 1H), 2.02 (s, 3H), 1.92-1.87 (m, 2H), 1.66-1.59 (m, 1H), 1.32 (s, 9H), 1.24-1.16 (m, 2H), 1.15-1.14 (m , 1 HOUR)

Step E. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2 - ((dimethylamino) methyl) -5-vinylcyclohexane-1-carboxamide and rac- (1R, 2R, 5R ) -1-acetamido-N-fferc-butyl) -2 - ((dimethylamino) methyl) -5-vinylcyclohexane-1-carboxamide.

Rac- (1R, 2R, 5R) -1-acetamido-N- (tert-butyl) -2-formyl-5-vinylcyclohexane-1-carboxamide (0.43 g, 1.46 mmol) was dissolved in 1.2 -dichloroethane (3 mL), Then, N, N-dimethylamine hydrochloride (0.14g, 1.76mmol) and triethylamine were added

(0.25 mL, 1.76 mmol) and the reaction mixture was stirred at room temperature for 1 hr. Then, sodium triacetoxyborohydride (0.62 g, 2.93 mmol) was added portionwise and the resulting reaction mixture was stirred overnight at room temperature. After this time, the mixture was quenched with 5% aqueous NaHCO3 (5 ml) and washed with dichloromethane (3 x 30 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, CH2Cl2 / MeOH 50: 1 to 20: 1) to provide the product as a mixture of diastereoisomers (overall yield: 146 mg, 31%). ESI + MS: m / z = 324.1 (M + 1) +, 346.2 (M + Na) +. Unique diastereoisomers were isolated in the order of elution:

rac- (1R, 2R, 5R) -1-acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5-vinylcyclohexane-1-carboxamide (36mg, 8%, colorless oil) . 1H NMR (700MHz, chloroform-d) 55.77-5.72 (m, 1H), 5.00-4.93 (m, 2H), 3.07-3.02 (m, 1H), 2 , 84 (d, J = 11.02 Hz, 1H), 2.54-2.50 (m, 1H), 2.30 (s, 6H), 2.12-2.08 (m, 1H), 2.01 (d, J = 13.29 Hz, 2H), 1.89 (s, 3H), 1.54-1.45 (m, 2H), 1.41-1.37 (m, 1H) , 1.36 (s, 9H), 1.29-1.26 (m, 1H).

rac- (1R, 2S, 5R) -1-acetamido-N- (fe / f-butyl) -2 - ((dimethylamino) methyl) -5-vinylcyclohexane-1-carboxamide (110mg, 23%, colorless oil). 1H NMR (700 MHz, chloroform-d) 55.74 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.01-4.90 (m, 2H), 3.43 -3.37 (m, 1H), 3.22 (d, J = 13.3 Hz, 1H), 2.27 (s, 6H), 2.20-2.13 (m, 1H), 2, 12-2.08 (m, 1H), 2.00 (d, J = 13.5Hz, 1H), 1.92 (s, 3H), 1.84-1.79 (m, 1H), 1 , 56-1.52 (m, 1H), 1.40-1.36 (m, 1H), 1.34 (s, 9H), 1.18 (d, J = 12.9 Hz, 2H).

Step F. rac- (1R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5- (2- (4,4,5,5 ) -tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide.

A mixture of dppe (7.7mg, 0.019mmol) and bis (1,5-cyclooctadiene) diiridium (I) dichloride (6.5mg, 0.0096mmol) in dichloromethane (2mL) was purged with argon. Separately, rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((dimethylamino) methyl) -5-vinylcyclohexane-1-carboxamide was dissolved in dry DCM (2 mL) ( purged with argon) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 µl, 0.739 mmol) was added dropwise. Then, the prepared solution was added dropwise to the aforementioned iridium catalyst mixture and dppe in DCM at RT. The reaction mixture was stirred at room temperature overnight. After that time, the reaction mixture was diluted with DCM (20 mL) and washed with 5% NaHCO3 (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH 50: 1 to MeOH) to provide rac- (1R, 2s, 5R) -1-acetamido-N- (fe / 'c-butyl) - 2 - ((dimethylamino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (50 mg, 34% ) as a colorless oil. ESI + MS: m / z = 452.1 (M + 1) +, 370.1 (M-Pin) +. 1H NMR (700 MHz, chloroform-d) 53.45-3.38 (m, 1H), 3.25-3.19 (m, 1H), 2.26 (d, J = 5.84 Hz, 6H ), 2.04-1.91 (m, 3H), 1.89 (s, 3H), 1.82-1.77 (m, 1H), 1.58-1.54 (m, 7H), 1.33 (s, 9H), 1.25 (s, 12H), 1.02-0.92 (m, 2H).

Step G. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride.

A mixture of rac- (1R, 2S, 5R) -1-acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5- (2- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (50 mg, 0.11 mmol) and 6 Nac HCl (10 mL) was heated under reflux for 6h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® followed by preparative HPLC (0.1-1% MeCN) to provide (after acidification with 6N HCl and lyophilization back) Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride (13.1 mg, 34%) as a white solid. ESI + MS: m / z = 273.0 (M + 1) +.

1H NMR (700 MHz, deuterium oxide) 53.28 (dd, J = 13.3, 2.6 Hz, 1H), 3.19 (dd, J = 13.2, 11.0 Hz, 1H), 2.92 (s, 3H), 2.85 (s, 3H), 2.24 (d, J = 11.58 Hz, 1H), 2.12 (s, 1H), 1.91-1.85 (m, 2H), 1.83-1.75 (m, 1H), 1.73-1.66 (m, 1H), 1.33-1.25

(m, 3H), 0.99-0.91 (m, 1H), 0.73 (dd, J = 9.1.7.2 Hz, 2H).

Example 18. Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) -cyclohexane-1-carboxylic acid dihydrochloride

Step A. rac- (1R, 2R, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5- (2- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide.

The title compound was obtained from rac- (1R, 2R, 5R) -1-acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5-vimlcidohexane-1-carboxamide (33 mg, 0.102 mmol) using the procedure described for the preparation of Example 17, step F. The crude product was purified by flash chromatography on silica gel (CH2Ch / MeOH 30: 1 to MeOH). Performance:

10 mg (22%); colorless oil. ESI + MS: m / z = 452.1 (M + 1) +, 474.0 (M + Na) +, 1H NMR (700 MHz, chloroform-d) 53.07 - 3.03 (m, 1H) , 2.84-2.78 (m, 1H), 2.55-2.50 (m, 1H), 2.29 (s, 6H), 2.15-2.06 (m, 1H), 2 .01-1.96 (m, 1H), 1.91 (d, J = 8.09 Hz, 3H), 1.82-1.77 (m, 1H), 1.58-1.54 (m , 7H), 1.35 (s, 9H), 1.25 (s, 12H), 0.92-0.90 (m, 2H).

Step B. Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride.

A mixture of (1R, 2R, 5R) -1-acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5- (2- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (10mg, 0.022 mmol) and 6 Nac HCl (5 mL) were heated at reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® and then preparative HpLC (0.1-10% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) 1.2 mg (16%) of a desired product as a white solid. ESI + MS: m / z = 273.2 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 53.31 - 3.25 (m, 1H), 2.96 (dd, J = 13.07, 3.13 Hz, 1H), 2.93 (s, 3H ), 2.85 (s, 3H), 2.68-2.63 (m, 1H), 2.22-2.16 (m, 1H), 1.87-1.81 (m, 1H), 1.72-1.62 (m, 2H), 1.60-1.54 (m, 1H), 1.52-1.48 (m, 1H), 1.39-1.31 (m, 3H ), 0.80-0.69 (m, 2H).

Example 19. Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid dihydrochloride

Step A. rac- (1S, 2R, 5R) -1-acetamido-N- (fe / 'c-butyl) -2-formyl-5-vinylcyclohexane-1-carboxamide

The title compound was prepared from ethyl (1R, 2S, 4R) -2-acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Example 17, step C) (0.287 g, 0.85 mmol, 1 equiv.), DIBAL-H (1M in DCM, 1.78 mL, 1.78 mmol, 2.1 equiv.), solvent: DCM (8 mL) using the same procedure as the described in Example 17, step D. A colorless oil was obtained (80 mg, 32%). ESI + MS: m / z = 317.2 (M + Na) +. 1H NMR (700 MHz, chloroform-d) 10.06 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 6.96 (s, 1H), 5.72 (ddd , J = 17.1, 10.4, 6.4 Hz, 1H), 5.05-4.95 (m, 2H), 3.18 3.12 (m, 1H), 3.05-2, 95 (m, 1H), 2.06 (s, 3H), 1.93-1.84 (m, 2H), 1.57-1.47 (m, 1H), 1.30 (s, 9H) , 1.27-1.19 (m, 2H), 1.18-1.10 (m, 1H).

Step B. rac- (1S, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((dimethylamino) methyl) -5-vinylcyclohexane-1-carboxamide.

The title compound was prepared from rac- (1S, 2R, 5R) -1-acetamido-N- (fe / 'c-butyl) -2-formyl-5-vinylcyclohexane-1-carboxamide (80 mg, 0 , 27 mmol, 1 equiv.), Dimethylamine hydrochloride (26.6 mg, 0.32 mmol, 1.2 equiv.), Triethylamine

(45 | j L, 0.32 mmol, 1.2 equiv.), Sodium triacetoxyborohydride (114 mg, 0.54 mmol, 2 equiv.), DCM (1.3 mL) using the same procedure as described in Example 17, step E. A single diastereoisomer was obtained as a colorless oil (60 mg, 58%). ESI + MS: m / z = 324.1 (M + 1) +, 346.2 (M + Na) +. 1H NMR (700 MHz, chloroform-d) 57.47 (s, 1H), 7.27 (s, 1H), 5.72 (ddd, J = 17.1, 10.5, 6.3 Hz, 1H ), 5.04-4.81 (m, 2H), 3.03 (d, J = 13.6 Hz, 1H), 2.85 (dd, J = 14.6, 2.9 Hz, 1H), 2.34 (dd, J = 14.6, 3.1 Hz, 1H), 2.28 (s, 6H), 2.01 (s, 3H) , 1.98 (dt, J = 13.1.3.2 Hz, 1H), 1.83-1.72 (m, 2H), 1.68-1.62 (m, 1H), 1.33 (s, 9H), 1.26 (t, J = 13.2Hz, 1H), 1.22-1.07 (m, 2H).

Stage C. rac- (1 S, 2S, 5R) -1-Acetamid-N- (tert-butyl) -2 - ((dimethyl) methyl) -5- ( 2- (4,4,5,5) -tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) ddohexane-1-carboxamide.

The title compound was prepared from rac- (1S, 2S, 5R) -1-acetamide-N- (tert-butyl) -2 - ((dimethylamine) met ¡L) -5-v¡n¡lc¡dohexane-1-carboxam¡da (60 mg, 0.186 mmol, 1 equ¡v.), B¡s (1,5-ddooctadene) d¡chloride d ¡¡R¡o (I) (4 mg, 0.0055 mmol, 0.03 equ¡v.), Dppe (5 mg, 0.011 mmol, 0.06 equ¡v.), 4.4.5 , 5-tetramethyl-1,3,2-dioxaborolane (56 ^ L, 0.37 mmol, 2 equiv.), DCM (1 1 mL) using the same procedure as that described in Example 17, step F. A single diastereoisomer was obtained as a colorless oil (25 mg, 30%).

ESI + MS: m / z = 452.1 (M + 1) +, 370.1 (M-Pn) +. 1H NMR (700 MHz, chloroform-d) 57.58 (s, 1H), 7.48 (s, 1H), 3.02-2-98 (m, 1H), 2.90-2.83 (m , 1H) 2.38-2.33 (m, 1H), 2.30 (s, 6H), 2.02 (s, 3H), 1.98-1.58 (m, 7H), 1.36 (s, 9H), 1.28 (s, 12H), 1.11-0.95 (m, 2H), 0.88 (m, 2H).

Stage D. Rac- acid dihydrochloride (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamine) methyl) ddohexane-1-carboxylic.

The title compound was prepared from rac- (1S, 2S, 5R) -1-acetamide-N- (tert-butyl) -2 - ((dimethylamine) methyl ) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) ddohexane-1-carboxamide (25 mg, 0.055 mmol), 6 Nac HCl (10 mL) using the same procedure as described in Example 17, step G. A single diastereoisomer was obtained as a white solid (2, 6 mg, 13%). ESI + MS: m / z = 255.0 (M-18) +. 1H NMR (700 MHz, deuterium oxide) 52.75 (dd, J = 12.9, 9.3 Hz, 1H), 2.67-2.61 (m, 1H), 2.60 (s, 6H), 2.17-2.09 (m, 1H), 1.86-1.78 (m, 2H), 1.73 (d, J = 13.3 Hz, 1H), 1, 47-1.40 (m, 1H), 1.38-1.22 (m, 4H), 1.01-0.90 (m, 1H), 0.72 (t, J = 8.1 Hz, 2H).

Example 20. 1-Amino-5- (2-boronoethyl) -2- (morpholinomethyl) cydohexane-1-carboxylic acid dihydrochloride

Stage A. 2- (morpholinomethyl) -5-v¡n¡lddohexan-1-one hydrochloride.

To the solution of 3-vinylcidohexanone (1 g, 8.05 mmol) in acetonitrile (10 mL) was added paraformaldehyde (0.29 g, 9.68 mmol), morpholine (695 µl, 8.05 mmol) and HCl ( conc) (0.77 mL, 9.26 mmol). The reaction mixture was stirred at 80 ° C for 3h and then at room temperature overnight. The solvent was evaporated under reduced pressure. The product was used in the next step without further purification. Obtained 1.8 g as orange oil (4: 1 mixture of diastereoisomers). Yield: 86%.

ESI + MS: m / z = 224.1 (M + 1) +; ESI-MS: m / z = 222.8 (M-1) -.

The main diastereoisomer:

1H NMR (700 MHz, DMSO-d6) 55.85 (ddd, J = 17.0, 10.4, 5.9 Hz, 1H), 5.08-4.96 (m, 2H), 3.96 - 3.84 (m, 6H), 3.57-3.49 (m, 1H), 3.44-3.31 (m, 1H), 3.18 (dq, J = 11.1, 5, 5 Hz, 1H), 3.11 (tt, J = 14.4, 8.9 Hz, 1H), 3.05 (dt, J = 9.6, 4.9 Hz, 1H), 3.04 - 2.95 (m, 1H), 2.87 (dt, J = 13.2, 4.1 Hz, 1H), 2.43 (d, J = 6.1 Hz, 1H), 2.37 (ddd , J = 13.0, 6.0, 3.1 Hz, 1H), 1.86 (dd, J = 11.4, 3.1 Hz, 1H), 1.65-1.55 (m, 1H ), 1.43 (qd, J = 13.1, 3.5 Hz, 1H).

Step B. 1-Acetamido-N- (tere-butyl) -2- (morpholinomethyl) -5-vinylcyclohexane-1-carboxamide.

To a mixture of 2- (morpholinomethyl) -5-vinylcyclohexan-1-one hydrochloride (1.8 g, 8.07 mmol), ammonium acetate (2.4 g, 32.28 mmol), 2.2, 2-Trifluoroethanol (10 mL), tere-butyl isocyanide (1.81 mL, 16.1 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with 5% NaHCO3. They were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (dichloromethane / methanol 50: 1 to 10: 1). Yield: 1.65 g (56%); an orange solid (single diastereomer). ESI + MS: m / z = 366.2 (M + 1) +; ESI-MS: m / z = 364.2 (M-1) -. 1H NMR (700 MHz, chloroform-d) 59.95 (s, 1H), 8.27 (s, 1H), 5.74 ( ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.03-4.86 (m, 2H), 3.74 (d, J = 12.6 Hz, 4H), 3 , 48 (dd, J = 13.7, 10.1 Hz, 1H), 3.24 (dt, J = 13.4, 2.3 Hz, 1H), 2.71 (s, 2H), 2, 42 (s, 2H), 2.26-2.16 (m, 2H), 2.13-2.07 (m, 1H), 2.03 (s, 3H), 1.83 (dtd, J = 12.6, 4.2, 2.3 Hz, 1H), 1.66-1.59 (m, 1H), 1.46-1.40 (m, 1H), 1.35 (s, 9H) , 1.18

(qd, J = 13.1, 5.3 Hz, 2H).

Step C. 1-Acetamido-N- (tere-butyl) -2- (morpholinomethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl ) cyclohexane-1-carboxamide.

A mixture of dppe (32 mg, 0.08 mmol), bis (1,5-cyclooctadiene) diiridium (I) dichloride (27 mg, 0.04 mmol) was dissolved in degassed dichloromethane (10 mL) under argon. Separately, a solution of 1-acetamido-N- (tere-butyl) -2- (morpholinomethyl) -5-vinylcyclohexane-1-carboxamide (490 mg, 1.34 mmol) in degassed dichloromethane (10 mL) was prepared and pinacolborane (291 µl, 2.01 mmol) was added dropwise. Then, the solution thus prepared was added dropwise to the above-mentioned mixture of bis (1,5-cyclooctadiene) diiridium (I) dichloride and dppe in dichloromethane. The reaction mixture was stirred at room temperature overnight. The crude product was purified by silica gel flash chromatography. (40: 1 to 5: 1 dichloromethane / acetone) to yield 95 mg (14%) of the desired product as a colorless oil (single diastereomer). ESI + MS: m / z = 494.7 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 59.94 (s, 1H), 8.29 (s, 1H), 3.77-3.66 (m, 4H), 3.47 (dd, J = 13 , 7, 10.4 Hz, 1H), 3.22 (d, J = 13.2 Hz, 1H), 2.68 (s, 2H), 2.38 (s, 2H), 2.18 (s , 3H), 2.17-2.07 (m, 2H), 1.99 (d, J = 0.9Hz, 1H), 1.82-1.77 (m, 1H), 1.63 1.56 (m, 1H), 1.39-1.35 (m, 1H), 1.32 (s, 9H), 1.31-1.25 (m, 1H), 1.24 (s, 12H), 1.23-1.21 (m, 1H), 1.01-0.92 (m, 2H), 0.82 (ddd, J = 17.0, 10.9, 6.2 Hz, 1H), 0.72

(ddd, J = 16.0, 11.0, 5.5 Hz, 1H).

Step D. 1-Amino-5- (2-boronoethyl) -2- (morpholinomethyl) cidohexane-1-carboxylic acid dihydrochloride.

1-Acetamido-N- (fe / 'c-butyl) -2- (morpholinomethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was dissolved ) ethyl) acidhexane-1-carboxamide (95 mg, 0.19 mmol) in 4 M HCl in dioxane (0.5 mL) and treated with 6 M HCl (aq) (2 mL). The reaction mixture was refluxed for 5 h. Then the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (0.1-10% acetonitrile) to provide 6.7 mg (9%) of a desired product as a colorless foam (single diastereomer). ESI + MS: m / z = 315.1 (M + 1) +; 297.1 (M-18) +.

1H NMR (700 MHz, deuterium oxide) 54.30 (s, 4H), 3.76-3.67 (m, 1H), 3.65 (s, 4H), 3.62-3.48 (m , 1H), 2.60-2.53 (m, 1H), 2.48 (t, J = 11.4 Hz, 1H), 2.30-2.10 (m, 3H), 2.09 - 1.97 (m, 1H), 1.71-1.50 (m, 3H), 1.33-1.21 (m, 1H), 1.11-1.05 (m, 2H).

Example 21. 1-Amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid dihydrochloride Step A. 2 - ((Benzyl (methyl) amino) methyl) -5-vinylcyclohexan-1-one hydrochloride.

The title compound was obtained in the same way as in Example 20, step A using 3-vinylddohexanone (i g;

8.05 mmol), paraformaldehyde (0.29 g, 9.68 mmol), N-benzyl-methylamine (1.04 mL, 8.05 mmol), HCl (conc) (0.77 mL;

9.26 mmol) and MeCN (10 mL). The crude product was purified by silica gel flash chromatography using DCM / MeOH (100: 1 to 30: 1). Yield: 1.5 g (63%); beige rubber (dr = 4: 1).

The main diastereoisomer:

ESI + MS: m / z = 258.2 (M + H) +, 280.2 (M + Na) +. 1H NMR (700 MHz, D2O) 57.51-7.44 (m, 5H), 5.83 (ddd, J = 16.7, 10.4, 6.1 Hz, 1H), 5.04-4 , 97 (m, 2H), 4.39-4.24 (m, 2H), 3.45 (dd, J = 13.3, 9.7 Hz, 1H), 3.04-2.82 (m , 2H), 2.79 (s, 3H), 2.48-2.32 (m, 3H), 2.07-2.02 (m, 1H), 1.92-1.88 (m, 1H ), 1.61-1.52 (m, 1H), 1.38 (qd, J = 13.0, 3.5 Hz, 1H). Step B. 1-Acetamido-2 - ((benzyl (methyl) amino) methyl) -N- (tere-butyl) -5-vinylcyclohexane-1-carboxamide.

To a mixture of 2 - ((benzyl (methyl) amino) methyl) -5-vinylcyclohexan-1-one hydrochloride (1.39 g, 4.73 mmol), ammonium acetate (1.46 g, 18.9 mmol), 2,2,2-trifluoroethanol (4 mL), tere-butyl isocyanide (1.1 mL, 9.46 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and then treated with 5% aqueous NaHCO3 (30 mL) and 1 M NaOH (10 mL). The resulting mixture was washed with ethyl acetate (3 x 30 mL). The combined organic layers were washed with 5% NHCO3 (10 mL), and brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using dichloromethane / methanol (20: 1). The fractions containing the desired product were combined, concentrated, and purified again using DCM / acetone (20: 1 to 1: 1). 540 mg were obtained as orange oil. Yield: 28% (dr = 2: 1).

The main diastereoisomer:

ESI + MS: m / z = 400.3 (M + H) +, 422.2 (M + Na) +. 1H NMR (700MHz, CDCh) 57.35-7.30 (m, 3H), 7.30-7.25 (m, 4H), 5.76 -5.71 (m, 1H), 5.01 - 4.96 (m, 1H), 4.94-4.89 (m, 1H), 3.64-3.58 (m, 2H), 3.39-3.30 (m, 1H), 3 , 27-3.19 (m, 1H), 2.23 (s, 3H), 2.13-2.02 (m, 2H), 1.87 (s, 3H), 1.84-1.79 (m, 1H), 1.64-1.52 (m, 3H), 1.45-1.40 (m, 1H), 1.31 (s, 9H).

Step C. 1-Acetamido-2 - ((benzyl (methyl) amino) methyl) -N- (tere-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide.

The title compound was prepared from 1-acetamido-2 - ((benzyl (methyl) amino) methyl) -N- (tere-butyl) -5-vinylcyclohexane-1-carboxamide hydrochloride (dr = 2: 1,620 mg , 1.42 mmol), using the procedure described in the preparation of Example 20, step C. The crude product was purified by flash chromatography on silica gel (DCM / acetone 20: 1 to 0: 1). Yield: 320 mg (43%, dr = 3: 1); brown oil. The major diastereoisomer: ESI + MS: m / z = 528.2 (M + H) +.

1H NMR (700 MHz, CDCh) 59.94 (bs, 1H), 8.23 (bs, 1H), 7.34-7.31 (m, 2H), 7.29-7.28 (m, 1H ), 7.27 - 7.25 (m, 2H), 5.73 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 4.99 (dt, J = 17.3 , 1.5 Hz, 1H), 4.94-4.90 (m, 1H), 3.64-3.59 (m, 2H), 3.39 3.34 (m, 1H), 3.26-3.22 (m, 1H), 2.23 (s, 3H), 2.20-2.16 (m, 2H), 1.87 (s, 3H), 1.84-1.80 (m, 1H), 1.65-1.60 (m, 1H), 1.44-1.40 (m, 1H), 1.36-1.33 ( m, 5H), 1.31 (s, 9H), 1.26 (s, 12H), 1.19-1.15 (m, 2H).

Step D. 1-Amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cidohexane-1-carboxylic acid dihydrodoride.

The title compound was prepared from 1-acetamido-2 - ((benzyl (methyl) amino) methyl) -N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) ethyl) cidohexane-1-carboxamide (125 mg, 0.33 mmol; dr = 3: 1), using the procedure described in the preparation of Example 20, step D. Crude product was purified by preparative HPLC (1-20 % MeCN in water). Yield: 15 mg (15%; dr = 3: 1); white solid.

The major diastereoisomer: ESI + MS: m / z = 214.0 (M-18 + H) +, 232.0 (M + H) +. 1H NMR (700 MHz, D2O) 57.51-7.48 (m, 3H), 7.47-7.45 (m, 2H), 4.41 (bd, J = 12.4 Hz, 1H), 4.32 (bd, J = 12.2 Hz, 1H), 3.24-3.18 (m, 2H), 2.88 (s, 3H), 2.27-2.18 (m, 2H) , 2.04-1.88 (m, 2H), 1.80-1.60 (m, 3H), 1.32-1.22 (m, 3H), 0.72-0.67 (m, 2H).

Example 22. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) -cyclohexane-1-carboxylic acid dihydrochloride

Step A. rac- (1R, 2S, 5R) -1-Acetamido-N- (te / 'c-butyl) -2- (pyrrolidin-1-ylmethyl) -5-vinylcyclohexane-1-carboxamide.

To a solution of ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (te / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Example 17, step C) (0.5 g , 1.48 mmol, 1 equiv.) In dry dichloromethane (10 mL) a solution of DIBAL-H (1M in DCM, 4.58 mL, 4.58 mmol, 3.1 equiv.) Was added dropwise to -78 ° C under argon. The reaction mixture was stirred at -78 ° C and monitored by TLC (hexane: AcOEt 1: 1). After 1 hr, the reaction mixture was quenched with glacial acetic acid (0.42 mL, 7.39 mmol, 5 equiv.) And stirred at -78 ° C for 10 min. Then, pyrrolidine (0.24 mL, 2.95 mmol, 2 equiv) was added dropwise and the cooling bath was removed. After 15 min, triacetoxyborohydride (1.25 g, 5.91 mmol, 4 equiv) was added portionwise and the resulting mixture was allowed to warm to room temperature and stirred for 1 h. After that time, TLC assay (DCM: MEOH 9: 1) revealed complete conversion of the aldehyde generated in situ. The mixture was diluted with dichloromethane and the organic layer was washed with 5% NaHCO3 (20 mL) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient elution, DCM: MeOH 100: 1 to 6: 1) to provide the corresponding product as separable diastereoisomers (overall yield 311 mg, 60%). e S i + MS: m / z = 350.2 (M + 1) +. The desired / • ac- (1R, 2S, 5R) -1-acetamido-N- (fe / 'c-butyl) -2- (pyrrolidin-1-ylmethyl) -5-vinylcyclohexane-1-carboxamide was isolated as a colorless oil (255 mg, 49%). 1H NMR (700 MHz, chloroform-d) 55.76 -5.67 (m, 1H), 5.02 - 4.86 (m, 2H), 3.74 - 3.66 (m, 1H), 3 , 23 (d, J = 13.4 Hz, 1H), 2.83-2.67 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.02 (m , 3H), 1.89 (s, 3H), 1.83-1.77 (m, 4H), 1.57-1.51 (m, 3H), 1.44-1.39 (m, 1H ), 1.34 (s, 9H), 1.28-1.23 (m, 1H).

Step B. / • ac- (2 - ((1R, 3R, 4S) -3-acetamido-3- (fe / 'c-butylcarbamoyl) -4- (pyrrolidin-1-ylmethyl) -cyclohexyl) ethyl) boronic acid .

A mixture of dppe (13.67 mg, 0.0343 mmol, 0.06 equiv.) And bis (1,5-cidooctadiene) -diiridium (I) dichloride (11.53 mg,

0.0172 mmol, 0.03 equiv.) In dichloromethane (5 mL) was purged with argon. Then the solution of / • ac- (1R, 2S, 5R) -1-acetamido-N- (fe / 'c-butyl) -2- (pyrrolidin-1-ylmethyl) -5-vinylcyclohexane was added dropwise -1-carboxamide (200 mg, 0.57 mmol,

1 equiv.) And 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (205 µl, 1.32 mmol, 2.3 equiv.) In DCM (5 mL). The reaction mixture was stirred at room temperature overnight. After that time, the reaction mixture was diluted with DCM (50 mL) and washed with 5% NaHCO3 (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Ch / MeOH 30: 1 to MeOH) to provide the desired product (126 mg, 56%) as a colorless oil. ESI + MS: m / z = 396.25 (M + 1) +. 1H NMR (700MHz, chloroform-d) 53.72-3.68 (m, 1H), 3.26-3.21 (m, 1H), 2.74-2.66 (m, 2H), 2 , 47-2.40 (m, 2H), 2.15-2.09 (m, 2H), 1.89 (s, 3H), 1.81-1.75 (m, 5H), 1.61 - 1.51 (m, 7H), 1.33 (s, 9H), 1.01-0.91 (m, 2H).

Step C. Rac- (1 ^, 2S, 5 ^) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride.

A mixture of / • ac- (2 - ((1R, 3R, 4S) -3-acetamido-3- (fe / f-butylcarbamoyl) -4- (pyrrolidin-1-ylmethyl) cyclohexyl) ethyl) boronic acid

(126 mg, 0.264 mmol) and 6 Nac HCl (15 mL) was heated under reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® and then by preparative HPLC (0.1-10% MeCN in water) to provide (after acidification and subsequent lyophilization) (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride (50 mg, 51%) as a white solid . ESI + MS: m / z = 299.2 (M + 1) +. 1H Rm N (700 MHz, deuterium oxide) 53.72-3.60 (m, 2H), 3.40-3.20 (m, 2H), 3.08 (dt, J = 11.7.8 , 1Hz, 1H), 2.98 (dt, J = 11.3, 8.4Hz, 1H), 2.24-2.16 (m, 1H), 2.15-2.06 (m, 2H), 2.06-2.00 (m, 1H), 2.00-1.93 (m, 2H), 1.94-1.80 (m, 2H), 1.79 (dd, J = 12.8, 3.3 Hz, 1H), 1.75-1.70 (m, 1H), 1.35-1.25 (m, 2H), 1.21 (t, J = 12.7 Hz , 1H), 0.92 (qd, J = 13.3, 12.9, 3.5 Hz, 1H), 0.76-0.69 (m, 2H).

Example 23. (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride (enantiomerically enriched).

Step A. Ethyl (+) - (4R) -4-Ethenyl-2-hydroxycyclohex-1-ene-1-carboxylate (enantiomerically enriched).

To a 100 mL round bottom flask was added [Rh (cod) Cl] 2 (178 mg, 0.36 mmol), (R) -BINAP (247 mg,

0.396 mmol), and potassium vinyl trifluoroborate (3.21 g, 0.024 mol). The flask was flushed with argon several times and degassed 1,4-dioxane (25 mL), triethylamine (5 mL, 0.036 mole), water (12.5 mL) were added. After stirring the resulting mixture for 10 min at room temperature, ethyl 2-oxocyclohex-3-ene-1-carboxylate (Example 17, step A) (2.0 g, 0.012 mol) was added. The reaction mixture was stirred at room temperature for 96 h. I know separated the layers. The aqueous layer was washed with ethyl acetate (2 x 40 mL). The combined organic layers were washed with 0.5M aqueous HCl (20 mL), and brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane / AcOEt (100: 1 to 50: 1) to yield 0.60 g (25%) of the desired product as a yellow oil. ESI + MS: m / z = 350.2 (M + 1) +. [a] D = 32.63 (c = 0.8 in CHCla). 1H NMR (700 MHz, chloroform-d) 55.91 -5.70 (m, 1H), 5.16-4.90 (m, 2H), 4.22 (qd, J = 7.1, 0, 5Hz, 2H), 2.45-2.30 (m, 3H), 2.24-2.12 (m, 2H), 1.89-1.74 (m, 1H), 1.45-1 , 18 (m, 5H).

Step B. Ethyl (1R, 2R, 4R) -2-Acetamido-2- (tere-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (88% ee.).

The title compound was obtained in the same way as in Example 17, step C using enantiomerically enriched ethyl (+) - (4R) -4-ethenyl-2-hydroxycyclohex-1-ene-1-carboxylate (0.5 g, 2.55 mmol), ammonium acetate (0.79 g, 10.2 mmol), 2,2,2-trifluoroethanol (2 mL) and tere-butyl isocyanide (0.58 mL, 5.1 mmol ). The crude product was purified by silica gel flash chromatography using hexane / AcOEt (30: 1 to 5: 1) to provide 300 mg (35%) of the desired product as a white solid. ESI + MS: m / z = 339.1 (M + 1) +, 361.1 (M + Na) +. 1H NMR (700 MHz, chloroform-d) 58.10 (s, 1H), 7.57 (s, 1H), 5.72 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H ), 5.03 - 4.91 (m, 2H), 4.20 (ddq, J = 59.5, 10.8, 7.1 Hz, 2H), 3.29 (d, J = 13.8 Hz, 1H), 2.28 (dd, J = 12.4, 4.4 Hz, 1H), 2.14 (dq, J = 11.6, 4.2, 3.6 Hz, 1H), 2 , 11-2.02 (m, 2H), 1.99 (s, 3H), 1.85-1.80 (m, 1H), 1.33-1.30 (m, 13H), 1.10 (qd, J = 13.2, 4.4 Hz, 1H).

Step C. (1R, 2S, 5R) -1-Acetamido-N- (tere-butyl) -2- (pyrrolidin-1-ylmethyl) -5-vinylcyclohexane-1-carboxamide (enantiomerically enriched).

The title compound was obtained in the same way as in Example 22, step A using ethyl (1R, 2R, 4R) -2-acetamido-2- (te / f-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (200 mg, 0.59 mmol), DIBAL-H (1M in DCM, 1.83 mL,

1.83 mmol), glacial acetic acid (169 □ L, 2.95 mmol), pyrrolidine (98 □ L, 1.18 mmol, 2 equiv.), Triacetoxyborohydride (0.50 g, 2.36 mmol), DCM (3 mL). Work-up: the reaction mixture was diluted with DCM (50 mL) and washed with 1M NaOH (2 x 5 mL) and brine (10 mL). The crude product was purified by silica gel flash chromatography using DCM / MeOH (100: 1 to 10: 1) to provide 147 mg (71%) of the desired product as a colorless oil. 1H NMR (700 MHz, chloroform-d) 55.76 -5.67 (m, 1H), 5.02 - 4.86 (m, 2H), 3.74 - 3.66 (m, 1H), 3 , 23 (d, J = 13.4 Hz, 1H), 2.83-2.67 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.02 (m , 3H), 1.89 (s, 3H), 1.83-1.77 (m, 4H), 1.57-1.51 (m, 3H), 1.44-1.39 (m, 1H ), 1.34 (s, 9H), 1.28-1.23 (m, 1H).

Step D. (1R, 2S, 5R) -1-Acetamido-N- (tere-butyl) -2- (pyrrolidin-1-ylmethyl) -5- (2- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (enantiomerically enriched).

The title compound was obtained in the same way as in Example 22, step B, using (1R, 2S, 5R) -1-acetamido-N- (tere-butyl) -2- (pyrrolidin-1-ylmethyl) - 5-vinylcyclohexane-1-carboxamide (114 mg, 0.33 mmol), dppe (8 mg, 0.02 mmol) and bis (1,5-cyclooctadiene) diiridium (I) dichloride (6.7 mg, 0, 01 mmol), a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (71 µl,

0.49 mmol), DCM (1.5 mL). The crude product was purified by silica gel flash chromatography using DCM / acetone (30: 1 to 1: 1) to provide 93 mg (59%) of the desired product as a pale yellow oil. ESI + MS: m / z = 478.4 (M + 1) +.

1H NMR (700MHz, chloroform-d) 53.72-3.68 (m, 1H), 3.26-3.21 (m, 1H), 2.74-2.66 (m, 2H), 2 , 47-2.40 (m, 2H), 2.15-2.09 (m, 2H), 1.89 (s, 3H), 1.81-1.75 (m, 5H), 1.61 - 1.51 (m, 7H), 1.33 (s, 9H), 1.27 (s, 12H), 1.01-0.91 (m, 2H).

Step E. (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride (enantiomerically enriched).

The title compound was obtained in the same way as in Example 22, step C, using (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2- (pyrrolidin-1-ylmethyl) - 5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (85 mg;

0.178 mmol), 6 Nac HCl (5 mL). The crude product was purified by ion exchange chromatography on DOWEX® and then by preparative HPLC (0.1-1% MeCN in water, followed by acidification with 6M HCl and subsequent lyophilization) to provide 20 mg of dihydrochloride of the (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid (27%) as a white solid. ESI + MS: m / z = 299.2 (M + 1) +. [a] D = -0.5 (c = 0.238 in H2O). 1H NMR (700 MHz, deuterium oxide) 53.72-3.60 (m, 2H), 3.40-3.20 (m, 2H), 3.08 (dt, J = 11.7.8, 1Hz, 1H), 2.98 (dt, J = 11.3, 8.4Hz, 1H), 2.24-2.16 (m, 1H), 2.15-2.06 (m, 2H ), 2.06-2.00 (m, 1H), 2.00-1.93 (m, 2H), 1.94-1.80 (m, 2H), 1.79 (dd, J = 12 , 8, 3.3 Hz, 1H), 1.75-1.70 (m, 1H), 1.35-1.25 (m, 2H), 1.21 (t, J = 12.7 Hz, 1H), 0.92 (qd, J = 13.3, 12.9, 3.5 Hz, 1H), 0.76-0.69 (m, 2H).

Example 24. 1-Amino-2- (aminomethyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid dihydrochloride

Step A. Ethyl 1 - (((tert-Butoxycarbonyl) amino) methyl) -2-oxo-4-vinylcyclohexane-1-carboxylate.

To the mixture of 4-ethenyl-2-hydroxycyclohex-1-ene-1-carboxylate (1.0 g, 5.1 mmol), N-Boc- (tosylmethyl) amine (1.45 g, 0.51 mmol) and Cs2CO3 (5.31 g, 16.3 mmol) in acetonitrile, TBABr (0.16 g, 0.51 mmol) was added. The reaction mixture was stirred at room temperature overnight. After that time, the reaction was partitioned between water (25 mL) and AcOEt (30 mL). The layers were separated. The aqueous layer was washed with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 20 mL), brine (1 x 20 mL), dried over MgSO4, and concentrated in vacuo. The desired product was obtained as a brown oil (1.65 g, 99%). ESI + MS: m / z = 348.1 (M + Na) +, 226.1 (M-Boc + 1) +. 1H NMR (700 MHz, chloroform-d) 55.80 -5.72 (m, 1H), 5.11 -5.01 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H ), 3.57 (dd, J = 14.0, 6.5 Hz, 1H), 3.50 (dd, J = 13.9, 6.8 Hz, 1H), 2.68-2.55 ( m, 1H), 2.51-2.45 (m, 1H), 1.94-1.79 (m, 2H), 1.55 (s, 1H), 1.50-1.44 (m, 1H), 1.42 (s, 9H), 1.31-1.25 (m, 4H).

Step B. tert-Butyl ((2-Oxo-4-vinylcyclohexyl) methyl) carbamate.

The mixture of 1 - (((tert-butoxycarbonyl) amino) methyl) -2-oxo-4-vinylcyclohexane-1-carboxylate (0.59 g, 1.90 mmol), methanol

(10 mL) and 4M aqueous NaOH solution (2 mL) was stirred at room temperature overnight. After this time, the methanol was evaporated and the residue was washed with ethyl acetate (3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (elution gradient: hexane / AcOEt 10: 1 7: 1) to provide the product as a mixture of diastereoisomers (overall yield 452 mg, 94%). It is I + MS: m / z = 276.12 (M + Na) +, 154.0 (M-Boc + 1) +. The main diastereoisomer was isolated as a colorless oil

(357 mg, 74%) and was used in the next step. 1H NMR (700 MHz, chloroform-cf) 5.80 (ddd, J = 17.0, 10.4, 6.3 Hz, 1H), 5.07 -5.00 (m, 2H), 3.34 - 3.27 (m, 1H), 2.68-2.55 (m, 1H), 3.20-3.15 (m, 1H), 2.55-2.48 (m, 1H), 2 , 47-2.41 (m, 1H), 2.25-2.17 (m, 1H), 2.12 (ddd, J = 12.9, 5.9, 3.2 Hz, 1H), 2 0.00-1.94 (m, 1H), 1.63-1.57 (m, 1H), 1.45-1.43 (m, 10H).

Step C. ((2-Acetamido-2- (tere-butylcarbamoyl) -4-vinylcyclohexyl) methyl) tere-butyl carbamate.

To the stirred solution of tere-butyl ((2-oxo-4-vinylcyclohexyl) methyl) carbamate (357 mg, 1.41 mmol, 1 equiv.) And ammonium acetate (434 mg, 5.64 mmol, 4 equiv .) in 2,2,2-trifluoroethanol (1 mL), tere-butyl isocyanide was added dropwise

(317 pL, 2.82 mmol, 2 equiv.) Via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 1: 2) to provide the corresponding product as a mixture of diastereoisomers (overall yield: 555 mg, 99%). ESI + MS: m / z = 418.1 (M + Na) +, 296.1 (M-Boc + 1) +. The main diastereoisomer was isolated as a colorless oil (300 mg, 54%) and used in the next step. 1H NMR (700 MHz, chloroform-cf) 55.73 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.03-4.91 (m, 2H), 3.22 - 3.15 (m, 1H), 2.99-2.91 (m, 1H), 2.18-2.03 (m, 5H), 1.56-1.54 (m, 1H) 1, 47 (s, 9H), 1.33 (s, 9H), 1.31-1.26 (m, 3H), 1.18-1.07 (m, 2H).

Step D. ((2-Acetamido-2- (tere-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) methyl ) tere-butyl carbamate.

A mixture of dppe (18.1 mg, 0.045 mmol) and bis (1,5-cyclooctadiene) diiridium (I) dichloride (15.3 mg, 0.023 mmol) in dichloromethane (5 mL) was purged with argon. Then, the solution of tere-butyl ((2-acetamido-2- (terebutylcarbamoyl) -4-vinylcyclohexyl) methyl) carbamate (300 mg, 0.758 mmol) and 4,4,5,5-tetramethyl -1,3,2-Dioxaborolane (253 µl, 1.744 mmol) in DCM (5 mL) (argon purged). The reaction mixture was stirred at room temperature overnight. After that time, the reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography, on silica gel (CH2Ch / MeOH 100: 1) to provide the desired product (390 mg, 98%) as a colorless oil. ESI + MS: m / z = 546.2 (M + Na) +, 424.2 (M-Boc + 1) +. 1H NMR (700 MHz, chloroform-cf) 53.46 (dd, J = 15.5, 6.5 Hz, 1H), 3.16 (d, J = 13.2 Hz, 1H), 2.98- 2.91 (m, 1H), 2.07 (s, 3H), 2.06 2.00 (m, 1H), 1.81-1.74 (m, 2H), 1.59-1.57 (m, 1H), 1.46 (s, 9H), 1.35-1.32 (m, 1H), 1.31 (s, 9H), 1.30-1.26 (m, 2H), 1.24 (s, 12H), 0.95 (t, J = 12.9 Hz, 1H), 0.90-0.79 (m, 2H), 0.76-0.70 (m, 1H) .

Step E. 1-Amino-2- (aminomethyl) -5- (2-boronoethyl) cidohexane-1-carboxylic acid dihydrochloride.

A mixture of ((2-acetamido-2- (tere-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexyl) methyl ) tere-butyl carbamate (100 mg, 0.19 mmol) and 6 Nac HCl (5 mL) was heated under reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® and then preparative Hp Lc (0.1-1% MeCN in water) to provide the desired product

(20mg, 33%) as a white solid. ESI + MS: m / z = 245.15 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 53.29 (dd, J = 13.1, 3.0 Hz, 1H), 2.90 (dd, J = 13.1, 10.7 Hz, 1H), 2.25 (d, J = 11.8 Hz, 1H), 2.03-1.99 (m, 1H), 1.94-1.87 (m, 2H), 1.75-1.63 ( m, 2H), 1.34-1.25 (m, 3H), 0.97-0.88 (m, 1H), 0.76-0.70 (m, 2H).

Example 25. 1-Amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexane-1-carboxylic acid dihydrochloride

Step A. Ethyl 2- (2-Oxocyclohex-3-en-1-yl) acetate.

The title compound was prepared starting from 2-cyclohexen-1-one using the literature method (KF Podraza, RL Bassfield, J.Org . Chem., 54, 1989, 5919-5922). To a solution of 2M LDA in THF (28.4 mL, 56.8 mmol,

1.1 equiv.) At -78 ° C a solution of 2-cyclohexen-1-one (4.93 mL, 51.0 mmol, 1 equiv.) In THF was added dropwise

(10 mL) under argon. The solution was stirred for 15 min, and then a solution of ethyl bromoacetate (6.81 mL, 61.2 mmol, 1.2 equiv.) In t Hf (10 mL) was added dropwise and the reaction mixture resulting stirred for 2h at -78 ° C. The mixture was then diluted with diethyl ether and quenched with a saturated solution of NH4Cl. The mixture was allowed to warm to about 0 ° C and the aqueous layer was extracted with ether. The combined organic extracts were washed with saturated NH4Cl solution and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 5: 1) to provide the desired product (5.8 g, 62%) as a yellow liquid.

1H NMR (700 MHz, chloroform-d) 56.93 (dddd, J = 9.7, 5.5, 2.4, 1.4 Hz, 1H), 5.99 (ddd, J = 10.0, 2.9, 1.1 Hz, 1H), 4.18-4.44 (m, 2H), 2.90-2.77 (m, 2H), 2.51-2.35 (m, 2H) , 2.27-2.19 (m, 1H), 2.10 (dtdd, J = 13.1,4,7, 2.5, 1.5 Hz, 1H), 1.79 (tdd, J = 13.3, 11.3, 5.1 Hz, 1H), 1.23 (dt, J = 8.9, 7.2 Hz, 3H).

Step B. Ethyl 2- (2-Oxo-4-vinylcyclohexyl) acetate.

A solution of vinylmagnesium bromide (1M in THF) (33 mL, 33 mmol, 2 equiv.) And HMPA (13 mL) were added dropwise to a suspension of CuBr x Me2S (0.51 g, 2.47 mmol , 0.15 equiv.) In dry THF (60 mL) at -78 ° C for 15 min under argon. After stirring at -78 ° C for 15 min, a solution of ethyl 2- (2-oxocyclohex-3-en-1-yl) acetate (3.0 g, 16.5 mmol, 1 , 0 equiv.) And TMSCl (10.5 mL, 82.5 mmol, 5 equiv.) In dry THF (30 mL) for 30 min. The reaction mixture was stirred at -78 ° C for 2 h. The mixture was then quenched with saturated NH4Cl (100 mL) and extracted with AcOEt (3 x 100 mL). The organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (hexane / AcOEt 10: 1) to provide the desired product (overall yield 2.06 g, 59%) as a mixture of diastereoisomers. The main diastereoisomer was isolated as a colorless liquid and used in the next step. Yield: 1.45 g. 1H NMR (700 MHz, chloroform-d) 55.76 (ddd, J = 17.0, 10.4, 6.3 Hz, 1H), 5.02-4.92 (m, 2H), 4.09 (qd, J = 7.1, 4.4 Hz, 2H), 2.85-2.68 (m, 2H), 2.48-2.34 (m, 2H), 2.22 (td, J = 12.8, 1.0 Hz, 1H), 2.17-2.08 (m, 2H), 1.91 (ddd, J = 12.4, 5.9, 2.9 Hz, 1H), 1.62-1.52 (m, 1H), 1.41 (qd, J = 13.1.3.5 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H).

Step C. Ethyl 2- (2-Acetamido-2- (tere-butylcarbamoyl) -4-vinylcyclohexyl) acetate.

To the stirred mixture of ethyl 2- (2-oxo-4-vinylcyclohexyl) acetate (1.45 g, 6.90 mmol, 1 equiv.) And ammonium acetate (2.13 g, 27.6 mmol, 4 equiv.) in 2,2,2-trifluoroethanol (3 mL), tere-butyl isocyanide (1.50 mL, 13.8 mmol, 2 equiv.) was added via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 8: 1 to 2: 1) to provide the corresponding product as a mixture of diastereoisomers (overall yield 1.81 g, 74%) ESI + MS: m / z = 353.2 (M + 1) +, 375.1 (M + Na) +. The main diastereoisomer was isolated as a white solid and used in the next step. Yield: 1.60 g. 1H NMR (700 MHz, chloroform-d) 58.06 (s, 1H), 7.61 (s, 1H), 5.71 (dddd, J = 17.1, 10.6, 6.4, 4, 6Hz, 1H), 5.00-4.87 (m, 2H), 4.22-4.06 (m, 2H), 3.13-2.98 (m, 2H), 2.53 (dd , J = 16.8, 3.4 Hz, 1H), 2.49-2.37 (m, 1H), 2.28-2.15 (m, 1H), 2.00 (s, 3H), 1.94-1.74 (m, 2H), 1.67-1.57 (m, 1H), 1.32 (s, 9H), 1.28 (td, J = 7.1.6.1 Hz, 3H), 1.23-1.12 (m, 2H).

Step D. 1-Acetamido-N- (tere-butyl) -2- (2- (pyrrolidin-1-yl) ethyl) -5-vinylcyclohexane-1-carboxamide.

To a solution of 2- (2-acetamido-2- (tere-but¡lcarbamo¡l) -4-v¡n¡lc¡clohex¡l) ethyl acetate (0.71 g, 2.0 mmol, 1 equiv.) in dry dichloromethane (15 mL), a solution of DIBAL-H (1M in DCM, 6.2 mL, 6.2 mmol, 3.1 equiv.) was added dropwise at -78 ° C under argon . The reaction was stirred at -78 ° C and monitored by TLC (hexane: AcOEt 1: 1). After 1 hr, the reaction mixture was quenched with glacial acetic acid (0.57 mL, 10.0 mmol, 5 equiv.) And stirred at -78 ° C for 10 min. Then, pyrrolidine (0.33 mL, 4.0 mmol, 2 equiv) was added dropwise and the cooling bath was removed. After 15 min, triacetoxyborohydride (1.70 g, 8.0 mmol, 4 equiv.) Was added portionwise and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. After that time, TLC assay (DCM: MeOH 9: 1) revealed complete conversion of the aldehyde generated in situ. The mixture was diluted with dichloromethane and the organic layer was washed with 1N NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient elution, DCM: MeOh 20: 1 to 5: 1) to provide the corresponding product as a white solid. Yield: 0.176 g, (25%). ESI + MS: m / z = 364.3 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 55.73 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.03-4.87 (m, 2H), 3.26 -3.11 (m, 1H), 2.85-2.55 (m, 4H), 2.30-2.11 (m, 2H), 2.00-1.74 (m, 8H), 1 , 70-1.52 (m, 4H), 1.46-1.40 (m, 1H), 1.34 (s, 9H), 1.30-1.25 (m, 1H), 1.14 - 1.06 (m, 2H).

Step E. 1-Acetamid-N- (fe / 'c-but¡l) -2- (2- (p¡rrol¡d¡n-1-¡l) eth¡l) -5- (2 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyidohexane-1-carboxamide.

A mixture of dppe (6.2 mg, 0.0156 mmol, 0.06 equiv.) And bs (1,5-cdooctadene) dihydrochloride ( I) (5.2 mg,

0.0078 mmol, 0.03 equiv.) In dichloromethane (1 mL) was purged with argon (sparging). Then, the 1-acetamid-N- (fe / 'c-but¡l) -2- (2- (p¡rrol¡l) solution was added dropwise d¡n-1-¡l) eth¡l) -5-v¡n¡lc¡clohexane-1-carboxam¡da (94 mg, 0.26 mmol, 1 equ¡v.) and 4.4.5 , 5-tetramethyl-1,3,2-dioxaborolane (75 pL, 0.52 mmol, 2 equiv.) In DCM (1 mL) (argon purged). The reaction mixture was stirred at room temperature overnight. After that time, the reaction mixture was diluted with DCM (20 mL) and washed with 5% NaHCO3 (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH 20: 1 to 5: 1) to yield a corresponding product (62 mg, 49%) as an acetaminophen. I color you. ESI + MS: m / z = 492.4 (M + 1) +, 410.3 (M-Pn) +. 1H NMR (700 MHz, chloroform-d) 53.22-3.15 (m, 1H), 2.66-2.54 (m, 4H), 2.12-2.05 (m, 2H), 1 , 98-1.72 (m, 10H), 1.70-1.54 (m, 6H), 1.44-1.38 (m, 1H), 1.32 (s, 9H), 1.24 (s, 12H), 1.17-1.11 (m, 1H), 0.95-0.89 (m, 2H).

Stage F. 1-am¡no-5- (2-boronoet¡l) -2- (2- (p¡rrol¡d¡n-1-¡l) et¡l acid dihydrochloride ) cyclohexane-1-carboxylic.

A mixture of 1-acetamide-N- (fe / 'c-but¡l) -2- (2- (p¡rrol¡d¡n-1-¡l) eth¡l) -5- (2 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) cyclohexane-1-carboxamida (62 mg, 0.126 mmol) and 6 Nac HCl (10 mL) was refluxed for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® and then by Preparative HPLC (0.1 - 10% MeCN in water) to provide (after acidification with 6M HCl and subsequent liofilization) 5.2 mg (11%) of the desired product as a colorless film. ESI + MS: m / z = 313.3 (M + 1) +, ESI-MS: m / z = 311.1 (M-1) -. 1H NMR (700 MHz, deuterium oxide) 53.64-3.65 (m, 2H), 3.31 (td, J = 12.4, 4.7 Hz, 1H), 3.12 (td, J = 12.3, 5.1 Hz, 1H), 3.05-2.96 (m, 2H), 2.19-2.13 (m, 1H), 2.11-2.04 (m, 2H), 1.98 1.89 (m , 3H), 1.87-1.76 (m, 3H), 1.67-1.57 (m, 2H), 1.54-1.46 (m, 1H), 1.32-1.24 (m, 2H), 1.22-1.15 (m, 1H), 0.90-0.81 (m, 1H) 0.75-0.68 (m, 2H).

General synthetic route for examples 26-37.

Example 26. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) acid hexanecarboxylic acid dihydrodoride

Step A. (1R, 2S, 5R) -1-Acetamido-N- (¡fe / 'c-butyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) -5-vinylcyclohexanecarboxamide

To a solution of ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 1, 400 mg, 1.18 mmol, 1 equiv.) In dry dichloromethane (30 mL) a solution of 1M DIBAL-H in DCM (3.66 mL, 3.66 mmol, 3.1 equiv.) Was added dropwise at -78 ° C under argon. The reaction mixture was stirred at -78 ° C and monitored by TLC (hexane: AcOEt 1: 1). After 1h, the reaction mixture was quenched with glacial acetic acid (0.34 mL, 5.90 mmol, 5 equiv.) And stirred at -78 ° C for 10 min. Then, a 4,4-dimethylpiperidine hydrochloride solution (441 mg, 2.96 mmol, 2.5 equiv.) And TEA (0.41 mL, 2.96 mmol, 2.5 equiv.) Were added dropwise. ) in 10 mL of DCM and the cooling bath was removed. After 15 min, sodium triacetoxyborohydride (1.0 g, 4.72 mmol, 4 equiv) was added portionwise and the resulting mixture was allowed to warm to room temperature and then stirred overnight. The mixture was diluted with dichloromethane and the organic layer was washed with 1N NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (DCM: MeOH 20: 1) to provide the corresponding product as a single diastereoisomer (310 mg, 64%, pale yellow oil). ESI + MS: m / z = 392.35 (M + 1) +, 1H Rm N (700 MHz, chloroform-cf) 510.44 (s, 1H), 8.23 (s, 1H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.04-4.83 (m, 2H), 3.40-3.35 (m, 1H), 3.25 - 3.20 (m, 1H), 2.38-2.05 (m, 4H), 1.96 (s, 3H), 1.61-1.45 (m, 2H), 1.42-1 , 33 (m, 8H), 1.32 (s, 9H), 1.19-1.12 (m, 2H), 0.93 (s, 6H).

Step B. (1R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) -5- (2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide

A mixture of dppe (18.3 mg, 0.046 mmol, 0.06 equiv.) And bis (1,5-cyclooctadiene) diiridium (I) dichloride (15.4 mg, 0.023 mmol, 0.03 equiv.) In dichloromethane (3 mL) was purged with argon (bubbling). Subsequently, the separately prepared solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22 mL, 1.53 mmol, 2 equiv.) And rac- (1R, 2S, 5R) - 1-acetamido-N- (β-tert-butyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) -5-vinylcyclohexanecarboxamide (300 mg, 0.76 mmol, 1 equiv.) In 3 mL of Dry CH2Cl2 was added successively at room temperature. The resulting mixture was stirred at room temperature overnight. After that time, the reaction mixture was diluted with DCM and washed with 5% NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 30: 1 to 9: 1) to provide the corresponding product as a single diastereoisomer (230 mg, 58%, pale yellow oil). ESI + MS: m / z = 520.5 (M + 1) +, 1H NMR (700 MHz, chloroform-d) 510.43 (s, 1H), 8.29 (s, 1H), 3.52 - 3.46 (m, 1H), 3.43-3.37 (m, 1H), 3.20 (d, J = 13.2 Hz, 2H), 2.44-1.98 (m, 2H) , 1.95 (s, 3H), 1.41-1.30 (m, 6H), 1.31 (s, 9H), 1.28-1.23 (m, 4H), 1.23 (s , 12H), 1.21 (d, J = 7.1 Hz, 2H), 0.93 (s, 6H), 0.90-0.84 (m, 2H), 0.83-0.68 ( m, 2H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) cyclohexanecarboxylic acid dihydrochloride

A mixture of rac- (1 R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) -5- (2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (100 mg, 0.19 mmol, 1 equiv.) And 6N aq HCl (15 mL) was heated to reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on a DOWEX ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the product as a single diastereoisomer (28.9 mg, 44%, white solid). ESI + MS: m / z = 341.35 (M + 1) +, 1H NMR (700 MHz, Deuterium Oxide) 53.58 - 3.43 (m, 2H), 3.42 - 3.35 (m , 1H), 3.27-3.14 (m, 2H), 3.12-3.05 (m, 1H), 2.33-2.27 (m, 1H), 2.24-2.16 (m, 1H), 2.01-1.87 (m, 3H), 1.83-1.74 (m, 2H), 1.73-1.66 (m, 3H), 1.42-1 , 30 (m, 3H), 1.08 (s, 3H), 1.06 (s, 3H), 1.04-0.96 (m, 1H), 0.85-0.78 (m, 2H ).

Example 27. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) cyclohexanecarboxylic acid dihydrochloride

Step A. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) -5-vinylcyclohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) -5-vinylcyclohexanecarboxamide is obtained in the same way as in Example 26, step A, using ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 1, 300 mg, 0.887 mmol, 1 equiv.), 1M DIBAL-H in DCM (2.75 mL, 2.75 mmol, 3.1 equiv.), Glacial acetic acid (0.25 mL, 4.43 mmol, 5 equiv.), 4- (4-chlorophenyl) -piperidine hydrochloride (515 mg, 2.22 mmol, 2.5 equiv.), TEA (0.31 mL, 2.22 mmol, 2.5 equiv.), Sodium triacetoxyborohydride (0.75 g, 3.55 mmol, 4 equiv.) and DCM (25 mL). The residue was purified by silica gel flash chromatography (DCM: MeOH 20: 1) to provide the corresponding product as a single diastereoisomer (324 mg, 73%, pale yellow oil). ESI + MS: m / z = 474.3 (M + 1) +, 1H NMR (700 MHz, chloroform-d) 10.28 (s, 1H), 8.26 (s, 1H), 7.29 - 7.25 (m, 2H), 7.12-7.07 (m, 2H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.01 - 4.87 (m, 2H), 3.45 (dd, J = 13.7, 10.6 Hz, 1H), 3.28-3.21 (m, 2H), 2.96 (d, J = 11.8 Hz, 2H), 2.56-2.50 (m, 1H), 2.27 (td, J = 11.9, 2.4 Hz, 1H), 2.22-2.11 ( m, 2H), 2.01 (s, 3H), 1.97-1.90 (m, 2H), 1.69-1.61 (m, 2H), 1.62-1.57 (m, 2H), 1.41-1.32 (m, 2H), 1.33 (s, 9H), 1.28-1.07 (m, 2H).

E cap B. ra c - (1 ^, 2 S, 5 ^) -1 -A ce ta m id o -N - (fe rc -bu til) -2 - ((4 - (4 -do ro fe n il) p ip er id in -1 - il) metil) -5 - (2 - (4, 4, 5, 5 - te tra me til-1, 3, 2 -d io xa bo ro la n -2 -N) e til) c id ohe xa no ca rb o xa m id a

The title compound rac- (1 ^, 2S, 5 ^) - 1-acetamido-N- (tert-butyl) -2 - ((4- (4-dorophenyl) piperidin-1-yl) methyl) -5- (2- (4,4,5,5-tetramethiM, 3,2-dioxaborolan-2-N) etN) d-dohexanecarboxamide was obtained in the same way as in Example 26, step B, using rac- (1R, 2S, 5R) -1-acetamido-N- (fe / 'c-but¡l) -2 - ((4- (4-dorofeml) piperidin-1-¡l) methyl) -5-vinylcyclohexanecarboxamide (324 mg, 0.685 mmol, 1 equiv.), dppe (16.4 mg, 0.04L mmol, 0.06 equiv.), bisO ^ -dclooctadiene ^ iiridium dichloride) (13.8 mg, 0.02055 mmol, 0 , 03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 mL, 1.37 mmol, 2 equiv.) And DCM (8 mL). The crude product was purified by silica gel column chromatography (gradient elution, CH2Ch / MeOH 30: 1 to 9: 1) to provide the corresponding product as a single diastereoisomer (251 mg, 61%, sticky pale yellow oil) . ESI + m S: m / z = 602.5 (M + 1) +, 1H NMR (700 MHz, Chloroform-d) 10.26 (s, 1H), 8.23 (s, 1H), 7, 30-7.25 (m, 2H), 7.12-7.08 (m, 2H), 3.51-3.41 (m, 2H), 3.30-3.18 (m, 2H), 3.01-2.91 (m, 1H), 2.57-2.48 (m, 1H), 2.31-2.21 (m, 1H), 2.15-2.06 (m, 2H ), 2.01 (s, 3H), 1.98-1.85 (m, 2H), 1.69-1.57 (m, 4H), 1.54 (s, 9H), 1.41- 1.32 (m, 2H), 1.32 (s, 12H), 1.28-1.07 (m, 2H), 1.02-0.89 (m, 2H), 0.88-0, 73 (m, 2H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-dorophenl) p¡per¡d acid dihydrochloride N-1-yl) methyl) cyclohexanecarboxylic

The title compound rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-dorophenil) piper) acid dihydrochloride d¡n-1-iOmethiOcyclohexanecarboxylic was obtained in the same way as in Example 26, step C, using (1R, 2s, 5R) -1-acetamide-N- (tert-butyl) -2- ( (4- (4-dorophenil) p¡per¡d¡n-1-¡l) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-¡l) ethyl) cyclohexanecarboxamide (89.0 mg, 0.15 mmol, 1 equiv.) And 6 Nac HCl (8 mL). The residue was purified by flash chromatography on resin resin. DOWEX® ion exchange (eluent, 0.1N ammonia in water) to provide (after acidification with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (15.6 mg, 25%, white solid). ESI + MS: m / z = 423.3 (M + 1) +, 1H NMR (700 MHz, Deuterium Oxide) 57.48 - 7.43 (m, 2H), 7.37 - 7.32 (m, 2H), 3.86-3.80 (m, 1H), 3.77-3.71 (m, 1H), 3.42-3.38 (m, 1H), 3.31-3.23 (m, 2H ), 3.16-3.08 (m, 1H), 3.03-2.95 (m, 1H), 2.34-2.28 (m, 1H), 2.27-2.15 (m , 3H), 2.10-1.90 (m, 5H), 1 , 85-1.75 (m, 1H), 1.43-1.31 (m, 3H), 1.08-0.98 (m, 1H), 0.85-0.80 (m, 2H) .

Example 28. Rac- (1 R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-didorobendl) (methyl ) amno) methyl) cyclohexanecarboxylic

Stage A. rac- (1R, 2S, 5R) -1-Acetamide-N- (tert-butyl) -2 - (((3,4-diorobendl) (methyl) amino ) methyl) -5-vinylcyclohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - (((3,4-diorobendl) (methyl) am¡ no) methyl) -5-vinylcyclohexanecarboxamide was obtained in the same way as in Example 26, step A, using rac- (1R, 2R, 4R) -2-acetamide-2- (tert-butylcarbam) ¡L) Ethyl -4-v¡n¡lddohexane-1-carboxylate (intermediate 1,500 mg, 1.48 mmol, 1 equiv.), 1M DIBAL-H in DCM (4.58 mL, 4, 58 mmol, 3.1 equiv.) Glacial acetic acid (0.42 mL, 7.40 mmol, 5 equiv.) ^^ - dichlorobenzOmethyl amine (0.70 g, 3.70 mmol, 2.5 equiv), triacetoxyborohydride sodium (1.25 g, 5.92 mmol, 4 equiv.) and DCM (11 mL). The residue was purified by silica gel flash chromatography (DCM: MeOH 20: 1) to provide the corresponding product as a single diastereoisomer (410 mg, 57%, pale yellow oil). ESI + MS: m / z = 468.35 (M + 1) +, 1H NMR (700 MHz, Chloroform-d) 59.57 (s, 1H), 8.21 (s, 1H), 7.44 - 7.31 (m, 2H), 7.07 (dd, J = 8.1.2.0 Hz, 1H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.06-4.82 (m, 2H), 3.66-3.51 (m, 2H), 3.24 (dd, J = 34.5, 13.2 Hz, 2H), 2 , 24 (s, 3H), 2.21-2.12 (m, 1H), 2.11-1.99 (m, 2H), 1.93 (s, 3H), 1.83-1.77 (m, 1H), 1.64-1.57 (m, 1H), 1.44-1.37 (m, 1H), 1.28 (s, 9H), 1.20-1.12 (m , 2H).

Step B. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) -5- (2- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide was obtained in the same way as in Example 26, step B, using rac- (1R, 2S, 5R ) -1-acetamido-N- (tert-butyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) -5-vinylcyclohexanecarboxamide (400 mg, 0.86 mmol, 1 equiv.), dppe (20.5 mg, 0.0516 mmol, 0.06 equiv.), bis (1,5-cyclooctadiene) diiridium (I) dichloride (17.3 mg, 0.0258 mmol, 0.03 equiv.) , 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 mL, 1.72 mmol, 2 equiv.) And Dc M (4 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 40: 1 to 20: 1) to provide the corresponding product as a single diastereoisomer (430 mg, 84%, pale yellow oil). ESI + MS: m / z = 596.15 (M + 1) +, 1H NMR (700 MHz, Chloroform-d) 59.55 (s, 1H), 8.20 (s, 1H), 7.42 - 7.31 (m, 2H), 7.06 (dd, J = 8.1.2.0 Hz, 1H), 3.61-3.52 (m, 2H), 3.22 (dd, J = 45.3, 13.1 Hz, 2H), 2.22 (s, 3H), 2.12-2.02 (m, 2H), 1.92 (s, 3H), 1.80-1.73 (m, 1H), 1.68-1.53 (m, 3H), 1.41-1.29 (m, 4H), 1.27 (s, 9H), 1.24 (s, 12H), 1.01-0.88 (m, 2H), 0.84-0.67 (m, 2H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) cyclohexanecarboxylic acid hydrochloride

The title compound rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) cyclohexanecarboxylic acid hydrochloride was obtained in the same way as in Example 26, step C, using rac- ( 1 R, 2S, 5R) -1-acetamido-N- (ferf-butyl) -2 - (((3,4-dichlorobenzyl) (methyl ) amino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (40 mg, 0.067 mmol, 1 equiv.) and HCl 6 N aq (10 mL). The residue was purified by flash chromatography on a DOWEX ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (5 -50% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) a product as a single diastereoisomer (9.7 mg, 35%, white solid). ESI + MS: m / z = 417.35 (M + 1) +, 1H NMR (700 MHz, Deuterium Oxide) 57.93 - 7.61 (m, 2H), 7.46 (dd, J = 8 , 3.1.9 Hz, 1H), 4.69 -4.20 (m, 2H), 3.63-3.20 (m, 2H), 3.05-2.74 (m, 3H), 2.45-2.11 (m, 2H), 2.05-1.55 (m, 4H), 1.48-1.26 (m, 3H), 1.09-0.91 (m, 1H ), 0.88-0.68 (m, 2H).

Example 29. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid dihydrochloride

Step A. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2- (isoindolin-2-ylmethyl) -5-vinylcyclohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2- (isoindolin-2-ylmethyl) -5-vinylcyclohexanecarboxamide was obtained in the same way as in Example 26 , step A, using ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 1, 300 mg, 0.887 mmol, 1 equiv.) , 1M DIBAL-H in DCM (2.75 mL,

2.75 mmol, 3.1 equiv.), Glacial acetic acid (0.25 mL, 4.43 mmol, 5 equiv.), Isoindoline hydrochloride (340mg, 2.22 mmol, 2.5 equiv.), TEA (0.31 mL, 2.22 mmol, 2.5 equiv.), Sodium triacetoxyborohydride (0.75 g, 3.55 mmol,

4 equiv.). The residue was purified by silica gel flash chromatography (hexane / AcOEt 10: 1 to 2: 1) to provide the corresponding product as a single diastereoisomer (180 mg, 51%, sticky colorless solid). ESI + MS: m / z = 398.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 10.27 (s, 1H), 8.23 (s, 1H), 7.21 (s, 4H), 5.74 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.01-4.91 (m, 2H), 4.10 (d, J = 12.0 Hz, 2H), 3.90 - 3.84 (m, 2H), 3.23 (d, J = 13.4 Hz, 1H), 2.58 (d, J = 13.4 Hz , 1H), 2.28-2.19 (m, 1H), 2.12-2.05 (m, 1H), 1.88-1.80 (m, 1H), 1.67 (s, 3H ), 1.62-1.54 (m, 2H), 1.50-1.46 (m, 1H), 1.34 (s, 9H), 1.25-1.18 (m, 2H).

Step B. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2- (isoindolin-2-ylmethyl) -5- (2- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2- (isoindolin-2-ylmethyl) -5- (2- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide was obtained in the same way as in Example 26, step B, using rac- (1 R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2- (isoindolin-2-ylmethyl) -5-vinylcyclohexanecarboxamide (180 mg, 0.45 mmol, 1 equiv.), dppe (11 mg, 0.027 mmol, 0.06 equiv.), dichloride bis (1,5-cyclooctadiene) diiridium (I) (9 mg, 0.013 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 mL, 0 , 90 mmol, 2 equiv.) And DCM (6 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 100: 1 to 20: 1) to provide the corresponding product as a single diastereoisomer (145 mg, 60%, colorless, sticky solid) . ESI + MS: m / z = 526.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 10.24 (s, 1H), 8.25 (s, 1H), 7.20 (s, 4H), 4.09 (d, J = 12.0 Hz , 2H), 3.88 (d, J = 11.4 Hz, 2H), 3.21 (d, J = 13.2 Hz, 1H), 2.56 (d, J = 15.3 Hz, 1H ), 2.14 (dd, J = 13.8, 9.3 Hz, 1H), 1.90 (s, 1H), 1.83-1.78 (m, 1H), 1.65 (s, 3H), 1.49-1.40 (m, 2H), 1.33 (d, J = 5.9Hz, 9H), 1.29 (d, J = 4.5Hz, 1H), 1, 24 (d, J = 2.8 Hz, 12H), 1.04 - 0.93 (m, 2H), 0.89 (t, J = 6.3 Hz, 1H), 0.86 - 0.68 (m, 3H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid dihydrochloride

The title compound rac- (7R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26 , step C, using rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2- (isoindolin-2-ylmethyl) -5- (2- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (65 mg, 0.15 mmol, 1 equiv.), 6N HClac (20 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with 6N HCl and subsequent lyophilization) a product as a single diastereomer (30 mg, 49% , off-white solid). ESI + MS: m / z = 347.3 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 57.40 - 7.33 (m, 4H), 5.00 - 4.79 (m, 2H), 4.61 - 4.41 (m, 2H), 3 , 63 (s, 1H), 3.51 (d, J = 12.9 Hz, 1H), 2.26-2.14 (m, 2H), 2.02-1.95 (m, 1H), 1.92-1.80 (m, 2H), 1.76-1.66 (m, 1H), 1.32-1.26 (m, 3H), 1.00-0.92 (m, 1H ), 0.76-0.71 (m, 2H).

Example 30. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride

Step A. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2 - ((diethylamino) methyl) -5-vinylcyclohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((diethylamino) methyl) -5-vinylcyclohexanecarboxamide was obtained in the same way as in Example 26, Step A, using ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 1,500 mg, 1.48 mmol, 1 equiv.), 1M DIBAL-H in DCM (4.58 mL,

4.58 mmol, 3.1 equiv.) Glacial acetic acid (0.42 mL, 7.40 mmol, 5 equiv.), Diethylamine (0.31 mL, 2.95 mmol, 2 equiv), sodium triacetoxyborohydrogen ( 1.25 g, 5.92 mmol, 4 equiv.). The residue was purified by silica gel flash chromatography (DCM: MeOH 20: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 3: 1, (0.43 g, 82%, sticky colorless solid) . It is I + MS: m / z = 352.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 10.70, 7.69 [(2s, 1H, two diastereoisomers)], 8.39, 7.45 [(2s, 1H, two diastereoisomers)], 5.72 [(dddd, J = 17.1, 10.3, 6.5, 5.0 Hz, 1H, two diastereoisomers)], 5.01-4.96 [(m, 1H, two diastereoisomers)], 4, 94-4.90 [(m, 1H, two diastereoisomers)], 3.76-3.52 [(m, 1H, two diastereoisomers)], 3.26-3.12 [(m, 1H, two diastereoisomers) ], 2.68 (dq, J = 12.8, 7.3 Hz, 2H), 2.25 (dq, J = 12.8, 6.9 Hz, 2H), 2.17 (td, J = 13.3, 4.4 Hz, 1H), 2.07 (dd, J = 13.9, 1.9 Hz, 1H), 1.96, 1.91 [(2s, 3H, two diastereoisomers)], 1.83-1.70 (m, 1H), 1.54 (tdd, J = 10.5, 4.1, 1.9 Hz, 1H), 1.38-1.35 (m, 2H), 1.34, 1.31 [(2s, 9H, two diastereoisomers)], 1.23-1.12 (m, 2H), 1.05 (t, J = 7.1 Hz, 6H).

Step B. rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((diethylamino) methyl) -5- (2- (4,4,5,5) -tetramethyl -1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide and rac- (2 - ((1 R, 3R, 4S) -3-acetamido-3- (tert-butylcarbamoyl) -4 - ((diethylamino) acid ) methyl) cyclohexyl) ethyl) boronic

The title compounds were obtained in the same way as in Example 26, step B, using rac- (1R, 2S, 5R) -acetamido-N- (tert-butyl) -2 - ((diethylamino) methyl) - 5-vinylcyclohexanecarboxamide (Intermediate 1,200 mg, 0.57 mmol, 1 equiv.), Dppe (13 mg, 0.034 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (11 mg , 0.017 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 mL, 1.42 mmol, 2.5 equiv.) And Dc M (6 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 50: 1 to 5: 1) to provide the corresponding products as single diastereoisomers (0.16 g, 82%). Product as an ester of pinacol (80 mg, sticky pale yellow solid). ESI + MS: m / z = 480.6 (M + 1) +. Partially during purification by column chromatography on silica gel, the pinacol ester is removed. Product as a boronic acid (80 mg, yellowish foam). ESI + MS: m / z = 398.4 (M + 1) + 1H NMR (700 MHz, Chloroform-cf) 510.72, 10.69 [(2s, 1H, two rotamers)], 8.37, 8, [(2s, 1H, two rotamers)], 3.63-3.57 (m, 1H), 3.49 (d, J = 3.9 Hz, 1H), 3.27-3.20 (m , 1H), 2.67 (dq, J = 14.2, 7.1.6.5 Hz, 2H), 2.29-2.21 (m, 2H), 2.14-2.03 (m , 2H), 1.91.1.90 [(2s, 3H, two rotamers), 1.81-1.75 (m, 1H),

1.56-1.47 (m, 2H), 1.31 (s, 9H), 1.24 (d, J = 17.2 Hz, 2H), 1.05 (t, J = 7.1 Hz , 6H), 1.00-0.91 (m, 2H), 0.89-0.69 (m, 2H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride

The title compound rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26, step C, using rac- (2 - ((1R, 3R, 4S) -3-acetamido-3- (tert-butylcarbamoyl) -4 - ((diethylamino) methyl) cyclohexyl) ethyl) boronic acid (80 mg, 0, 20 mmol, 1 equiv.), 6N aq HCl

(20 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (60 mg, 80% , white solid). ESI + MS: m / z = 301.4 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.34-3.05 (m, 6H), 2.26-2.21 (m, 1H), 2.08 (d, J = 9.2 Hz, 1H ), 1.92-1.85 (m, 2H), 1.79 (qd, J = 14.3, 13.7, 4.1 Hz, 1H), 1.75-1.66 (m, 1H ), 1.28 (ddd, J = 12.2, 7.1, 3.6 Hz, 3H), 1.23 (q, J = 7.4 Hz, 6H), 0.96-0.88 ( m, 1H), 0.72

(dd, J = 9.3, 7.0 Hz, 2H).

Example 31. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid dihydrochloride

E cover A. rac- (1 R, 2S, 5 R) -1 -A ce ta m ¡do-N - (te rc -bu t¡l) -2 - (p ¡per¡d ¡n -1 -¡lm et ¡L) -5 -v ¡n ¡lc ¡c loh exan oca rboxa m ¡da

The title compound rac- (1R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2- (p¡per¡d¡n-1-lmethyl) -5 -v¡n¡lc¡clohexanecarboxam¡da was obtained in the same way as in Example 26, step A, using rac-2 - ((1S, 2R, 4R) -2-acetamid-2- ( tert-butylcarbamoil) -4-v¡n¡lc¡clohex¡l) ethyl acetate (Intermediate 1, 0.3 g, 0.88 mmol, 1 equiv.), DlBAL-H 1M in DCM (2.74 mL, 2.74 mmol, 3.1 equiv.), Glacial acetic acid (0.25 mL, 4.42 mmol, 5 equiv.), p¡per¡na (0.17 mL, 1.77 mmol, 2 equ¡v.), sodium trioxy borohydride (0.75 g, 3.54 mmol, 4 equ¡ v.), dry DCM (30 mL). The residue was purified by silica gel flash chromatography (gradient elution DCM: MeoH 100: 1 to 15: 1) to provide the corresponding product rac- (1R, 2S, 5R) -1 -acetam¡do-N- (tert-but¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) -5-v¡n¡lc¡dohexanecarboxam¡da as a diet Single isomer (0.14g, 43%, white solid). e S i + MS: m / z = 364.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 510.42 (s, 1H), 8.24 (s, 1H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H ), 5.03 -4.85 (m, 2H), 3.33 (ddd, J = 13.9, 10.7, 5.4 Hz, 1H), 3.22 (dt, J = 13.2 , 2.3 Hz, 1H), 2.21-2.03 (m, 3H), 1.97 (s, 3H), 1.80 (dtt, J = 12.4, 4.1.2.2 Hz, 1H), 1.64-1.40 (m, 10H), 1.38-1.34 (m, 2H), 1.32 (s, 9H), 1.14 (qd, J = 13, 4.0 Hz, 2H).

Stage B. rac- (1R, 2S, 5R) -1-Acetam¡do-N- (tert-but¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) -5- (2- (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamide

The title compound rac- (1R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2- (p¡per¡d¡n-1-lmethyl) -5 - (2- (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamida was obtained in the same way as in Example 26, step B, using rac- (1R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2- (p¡per¡d¡n-1-¡lmet ¡L) -5-v¡n¡lc¡clohexanecarboxam¡da (0.14g, 0.38 mmol, 1 equ¡v.), Dppe (0.009 g, 0.02 mmol, 0.06 equ¡v.) , b¡s (1,5-cyclooctadene) d¡¡r¡d¡o (I) chloride (0.008 g, 0.01 mmol, 0.03 equiv.), 4, 4,5,5-tetramethyl-1,3,2-dioxaborolane (0.073 mL, 0.50 mmol, 1.3 equiv). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 100: 1 to 10: 1) to provide the corresponding product (1R, 2S, 5R) - 1-acetamide-N- (tert-butyl) -2- (p¡per¡d¡n-1-¡lmeth¡l) -5- (2- (4,4,5,5-tetramet ¡L-1,3,2-d¡oxaborolan-2-¡l) eth¡l) cyclohexanecarboxam¡da as a single diastereomer (0.11 g, 5 8%, solid yellow). ESI + MS: m / z = 492.5 (M + 1) +, 410.4 (MP¡n + 1) +. 1H NMR (700 MHz, Chloroform-d) 510.41 (s, 1H), 8.31 (s, 1H), 3.40-3.29 (m, 1H), 3.25-3.18 (m , 1H), 2.73-2.41 (m, 2H), 2.39-2.13 (m, 2H), 2.13-2.02 (m, 2H), 1.96 (s, 3H ), 1.82-1.74 (m, 1H), 1.61-1.51 (m, 7H), 1.51-1.38 (m, 2H), 1.34-1.32 (m , 3H), 1.31 (br s, 6H), 1.31-1.28 (m, 1H), 1.27 (s, 1H), 1.27-1.25 (m, 1H), 1 , 24 (s, 1H), 1.23 (s, 9H), 0.99 - 0.90 (m, 2H), 0.90 - 0.85 (m, 1H), 0.84 - 0.76 (m, 1H), 0.72 (ddd, J = 16.2, 11.2, 5.2 Hz, 1H).

Stage C. Rac- acid dihydrochloride (1R, 2S, 5R) -1-amino-5- (2-boronoet¡l) -2- (p¡per¡d¡n-1 -¡Lmet¡l) cyclohexanecarboxylic

The title compound rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡perd¡n- 1-l-methyl) cyclohexanecarboxylic was obtained in the same way as in Example 26, step C, using the compound rac- (1R, 2S, 5R) -1-acetamide-N- (tert-but¡l) -2- (p¡per¡d¡n-1-¡lmetal) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamida (0.11 g, 0.22 mmol, 1 equiv.), 6N HClac (3 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC. goes (0.1 - 1% MeCN in water) to provide (after acidification with 6N HCl and subsequent liquefying) the hydrochloride product of acid (1R, 2S, 5R) -1-amino-5- (2-boronoet¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) cyclohexanecarboxylic (0.033 g, 43%, white solid). ESI + MS: m / z = 313.1 (M + 1) +. ESI-MS: m / z = 311.0 (M-1) -. 1H NMR (700 MHz, Deuterium oxide) 53.54 (d, J = 12.5 Hz, 1H), 3, 46 (d, J = 12.2 Hz, 1H), 3.27 (dd, J = 13.6, 2.3 Hz, 1H), 3.08 (dd, J = 13.6, 10.6 Hz , 1H), 2.97 (td, J = 12.3, 3.2 Hz, 1H), 2.83 (td, J = 12.3, 3.1 Hz, 1H), 2.23 (ddd, J = 13.1.3.2, 1.8 Hz, 1H), 2.19-2.09 (m, 1H), 1.95-1.83 (m, 4H), 1.80 (td, J = 13.0, 3.6 Hz, 1H), 1.77-1.71 (m, 2H), 1.71-1.62 (m, 2H), 1.53-1.36 (m, 1H), 1.35-1.21 (m, 3H), 0.92 (qd, J = 13.1.3.9 Hz, 1H), 0.72 (dd, J = 9.0, 7, 3Hz, 2H).

Example 32. Acid o rac- (1R, 2S, 5R) -1 -am ¡no -5 - (2 -bo ro no et¡l) -2 - ((¡so p rop ¡l ( met¡l) am ¡no) met¡l) c ¡c lo hexa no ca rbo x fi¡co

Step A. rac- (1R, 2S, 5R) -1-Acetamid-N- (tert-butyl) -2 - ((sopropyl (methyl) amine) methyl) -5-v¡n¡lc¡clohexanecarboxam¡da

The title compound was prepared from rac- (1R, 2R, 4R) -2-acetamid-2- (tert-butylcarbamoyl) -4-v¡nlc¡clohexane-1 Ethyl carboxylate (Intermediate 1.50 mg, 1.48 mmol), using the procedure described in Example 26, step A. The crude product was purified by flash chromatography on gel silica (DCM / MeOH 40: 1 to 15: 1) to provide the desired product as a colorless oil (123 mg, 24%). ESI + MS: m / z = 352.5 (M + 1) +. 1H r Mn (700 MHz, CDCh) 5 10.71 (s, 1H), 8.34 (s, 1H), 5.75 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H ), 4.96 (ddt, J = 42.3, 10.4, 1.5 Hz, 2H), 3.64-3.56 (m, 1H), 3.24 (dt, J = 13.6 , 2.5 Hz, 1H), 2.84 (h, J = 6.6 Hz, 1H), 2.25 (s, 3H), 2.22-2.15 (m, 1H), 2.10 - 2.04 (m, 2H), 1.92 (s, 3H), 1.86-1.79 (m, 1H), 1.55-1.50 (s, 1H), 1.40-1 , 35 (m, 1H), 1.34 (s, 9H), 1.22-1.14 (m, 2H), 1.02 (dd, J = 26.3, 6.6 Hz, 6H).

Step B. Rac- (2 - ((1R, 3R, 4S) -3-acetamide-3- (tert-butycarbamyl) -4 - ((sopropıl (methyl ) am¡no) metal) cyclohex¡l) et¡l) boron¡co

The title compound was prepared from rac- (1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - ((sopropyl (methyl) amine) methyl) -5-vnilcyclohexanecarboxamide (120 mg, 0.34 mmol), using the procedure described in Example 26, step B. The crude product is purified by silica gel flash chromatography (DCM / MeOH 40: 1 to 0: 1) to provide the desired product

(80 mg, 59%) as a colorless oil. ESI + MS: m / z = 398.55 (M + 1) +, 396.3 (M-1) -. 1H NMR (700 MHz, chloroform-d) 10.67 (s, 1H), 8, 32 (s, 1H), 3.27-3.18 (m, 1H), 2.27 (s, 3H), 2.16-2.06 (m, 2H), 1.94 (s, 3H) , 1.83 - 1.75 (m, 1H),

1.44-1.34 (m, 2H), 1.33 (s, 9H), 1.30-1.22 (m, 4H), 1.11-0.92 (m, 8H), 0, 91-0.72 (m, 3H).

Stage C. Rac- (1 R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((sopropyl (methyl) amine) acid methyl) cyclohexanecarboxylic

The title compound was prepared from acid rac- (2 - ((1R, 3R, 4S) -3-acetamid-3- (tert-butycarbamoil) -4 - (( Sopropyl (methyl) amine) methyl) cyclohexyl) ethyl) boron (80 mg, 0.20 mmol), using the procedure described in Example 26, step C. The crude product was purified by ion exchange chromatography on DOWEX® to the desired product (36 mg, 60%) as a white solid. ESI + MS: m / z = 301.3 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 3.39-3.30 (m, 1H), 3.21-3.13 (m, 1H), 2.86-2.79 (m , 1H), 2.54 (s, 3H), 2.00-1.96 (m, 1H), 1.79-1.74 (m, 2H), 1.72-1.64 (m, 1H ), 1.52-1.47 (m, 1H), 1.46-1.39 (m, 1H), 1.27-1.17 (m, 2H), 1.14 (dd, J = 6 , 7, 3.6 Hz, 6H), 0.97 (t, J = 12.6 Hz, 1H),

0.92-0.83 (m, 1H), 0.69 (t, J = 8.1 Hz, 2H).

Example 33. Rac- acid dihydrochloride (1R, 2S, 5R) -1-amno-5- (2-boronoethyl) -2 - ((tertbutlamno) met¡ l) cyclohexanecarboxylic

E cover A. rac - (1 R, 2S, 5R) -1 -A ce tam ¡do -N - (te rc -but¡ l) -2 - ((te rc -but¡ la m¡no) metal) -5 -v ¡n ¡lc ¡c loh exan oca rbo xam ¡da

The title compound was prepared from rac- (1R, 2R, 4R) -2-acetamid-2- (tert-butylcarbamoyl) -4-v¡nlc¡clohexane-1 -carboxylate (Intermediate 1, 150 mg, 0.44 mmol), using the procedure described in the preparation of Example 26, step A. The crude product was purified by silica gel flash chromatography (DCM / MeOH 20: 1 to 0: 1)) to yield 30 mg (19%) of the desired product as a colorless oil. ESI + MS: m / z = 352.3 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 510.85 (s, 1H), 8.35 (s, 1H), 5.79 -5.63 (m, 1H), 5.08-4.86 (m , 2H), 3.48-3.39 (m, 1H), 3.31-3.19 (m, 1H), 2.75-2.56 (s, 1H), 2.30-2.18 (m, 2H), 2.16-2.03 (m, 1H), 1.97 (s, 3H), 1.90-1.76 (m, 1H), 1.45-1.40 (m , 2H), 1.35 (s, 9H), 1.22-1.16 (m, 1H), 1.12 (s, 9H).

Step B. rac- (1R, 2S, 5R) -1-Acetamid-N- (tert-butyl) -2 - ((tert-butylamine) methyl) -5- (2 - (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) c¡dohexanecarboxam¡da

The title compound was prepared from rac- (1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - ((tert-butyllamine) met L) -5-v¡n¡lddohexanecarboxamide (30 mg, 0.085 mmol), using the procedure described in the preparation of Example 26, step B. The crude product was purified by silica gel flash chromatography (DCM / MeOH 30: 1 to 0: 1)) to yield 20 mg (49%) of the desired product as a colorless oil. ESI + MS: m / z = 480.45 (M + 1) +. 1H Rm N (700 MHz, chloroform-d) 10.19 (s, 1H), 8.68 (s, 1H), 6.26 (s, 1H), 3.04-2.95 (m, 1H ), 2.95-2.87 (m, 1H), 2.70-2.58 (m, 1H), 2.56-2.48 (m, 1H), 2.09 (s, 3H), 1.89-1.80 (m, 1H), 1.70-1.63 (m, 1H), 1.44 (s, 9H), 1.38 (s, 9H), 1.34-1, 28 (m, 2H), 1.24 (s, 12H), 1.20-1.14 (m, 1H), 1.13-0.97 (m, 2H), 0.91 (t, J = 7.4 Hz, 1H), 0.85-0.70 (m, 2H).

Stage C. Rac- acid dihydrochloride (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((tertbutlamno) met¡ l) cyclohexanecarboxylic

The title compound was prepared from rac- (1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - ((tert-butyllamine) met ¡L) -5- (2- (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamide (17.5 mg, 0.036 mmol), using the procedure described in the preparation of Example 26, step C. The crude product was purified by ionic exchange chromatography with DOWEX® and , then, by preparative HPLC (0.1 - 1% MeCN in water) to provide (after acidification with 6M HCl and subsequent l¡of¡l¡ zacón) the desired product (2.2 mg, 16%) as a white solid. ESI + MS: m / z = 301.3 (M + 1) +, 323.3 (M + Na) +. 1H NMR (700 MHz, deuterium oxide) 53.29 (dd, J = 13.0, 3.0 Hz, 1H), 2.86 (dd, J = 12.9, 10.2 Hz , 1H), 2.23-2.17 (m, 1H), 1.98-192 (m, 1H), 1.88-1.82 (m, 2H), 1.80-1.71 (m , 1H), 1.70-1.62 (m, 1H), 1.30 (s, 9H), 1.29-1.21 (m, 3H), 0.94-0.83 (m, 1H ), 0.74-0.67 (m, 2H).

Example 34. Rac- acid dihydrochloride (1R, 2S, 5R) -2- (7-azabiclo [2.2.1] heptan-7-methyl) -1-am ¡No-5- (2-boronoet¡l) cyclohexanecarboxylic

Stage A. rac- (1R, 2S, 5R) -2- (7-Azabiclo [2.2.1] heptan-7-methyl) -1-acetamid-N- (tert-but ¡L) -5-v¡n¡lc¡clohexanecarboxam¡da

The title compound was prepared from rac- (1R, 2R, 4R) -2-acetamid-2- (tert-butylcarbamoyl) -4-v¡nlc¡clohexane-1 -carboxylate (Intermediate 1, 300 mg, 0.89 mmol), using the procedure described in the preparation of Example 26, step A. The crude product was purified by chromatography silica gel flash (DCM / MeOH 20: 1 to 2: 1)) to yield 85 mg (26%) of the desired product as a colorless oil. ESI + MS: m / z = 376.3 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 58.97 (s, 1H), 8.48 (s, 1H), 5.70 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H ), 5.02-4.90 (m, 2H), 4.04-4.01 (m, 1H), 3.93-3.90 (m, 1H), 3.51-3.36 (m , 2H), 3.20-3.08 (m, 2H), 2.57-2.40 (m, 2H), 2.24 (s, 3H), 2.22-2.17 (m, 1H ), 2.16-2.08 (m, 2H), 2.05-1.99 (d, J = 16.6 Hz, 1H), 1.83-1.69 (m, 5H), 1, 65-1.60 (m, 1H), 1.32 (s, 9H), 1.29-1.25 (m, 1H), 1.24-1.15 (m, 1H).

Stage B. /•ac-(1R,2S,5R)-2-(7-Azabicyclo[2.2.1 :) heptan-7-ilmethyl)-1-acetamido-N-(fe/'c-butyl)-5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cydohexanecarboxamide

The title compound was prepared from /•ac-(1R,2S,5R)-2-(7-azabicyclo[2.2.1 :)heptan-7-ylmethyl)-1-acetamido-N-(ferc-butyl^ -vinylcyclohexanecarboxamide (85 mg, 0.23 mmol), using the procedure described in the preparation of Example 26, step B. The crude product was purified by flash chromatography on silica gel (DCM / MeOH 30: 1 to 0: 1) to yield 40 mg (35%) of the desired product as a colorless oil ESI + MS: m / z = 504.4 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 59.00 (s, 1H), 8.45 (s, 1H), 4.08-4.02 (m, 1H), 3.95-3.90 (m, 1H), 3.56-3.50 (m, 1H) , 3.47-3.41 (m, 1H), 3.21-3.12 (m, 2H), 2.60-2.52 (m, 1H), 2.51-2.44 (m, 1H), 2.26 (s, 3H), 2.23-2.06 (m, 4H), 1.82-1.71 (m, 5H),

1.67-1.61 (m, 1H), 1.34 (s, 9H), 1.27 (s, 12H), 1.24-1.20 (m, 1H), 1.14-1, 07 (m, 1H), 1.04-0.97 (m, 1H), 0.95-0.88 (m, 1H), 0.86-0.79 (m, 1H), 0.77 - 0.70 (m, 1H).

Step C. Rac- (1R, 2S, 5R) -2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

The title compound was prepared from rac- (1R, 2S, 5R) -2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-acetamido-N- (tert-butyl) -5 - (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (40 mg, 0.079 mmol), using the procedure described in the preparation of Example 26, step C. The crude product was purified by DOw Ex ® ion exchange chromatography and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with 6M HCl and subsequent lyophilization) the desired product (22 mg, 70%) as a white solid. ESI + MS: m / z = 325.25 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 54.12 (t, J = 4.2 Hz, 1H), 4.08 (t, J = 4.6 Hz, 1H), 3.21 (dd, J = 13.8, 3.0 Hz, 1H), 3.03 (dd, J = 13.8, 10.1 Hz, 1H), 2.22-2.18 (m, 1H), 2.12-2 .06 (m, 1H), 2.05-1.91 (m, 5H), 1.91-1.85 (m, 1H), 1.85-1.72 (m, 5H), 1.71 - 1.63 (m, 1H), 1.31-1.19 (m, 3H), 0.92 (qd, J = 12.8, 3.8 Hz, 1H), 0.72 (dd, J = 9.0, 7.3 Hz, 2H).

Example 35. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclohexanecarboxylic acid dihydrochloride

Step A. / ac- (1 R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((3,4-dihydroisoquinolin-2 (1 H) -yl) methyl) -5-vinylcyclohexanecarboxamide

The title compound was prepared from rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 1, 300mg, 0.89mmol) , using the procedure described in the preparation of Example 101, step A. The crude product was purified by flash chromatography on silica gel (DCM / MeOH 100: 1 to 90: 1) to yield 88 mg (24%) of the desired product as a colorless oil. ESI + MS: m / z = 412.45 (M + 1) +, 434.5 (M + Na) +. 1H NMR (700 MHz, chloroform-d) 10.29 (s, 1H), 8.23 (s, 1H), 7.17-7.09 (m, 3H), 7.06-7.01 ( m, 1H), 5.73 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.06-4.87 (m, 2H), 3.83-3.73 ( m, 1H), 3.67-3.52 (m, 2H), 3.24-3.18 (m, 1H), 3.03-2.95 (m, 1H), 2.92 (t, J = 5.9 Hz, 2H), 2.70-2, 60 (m, 1H), 2.36-2, 29 (m, 1H), 2, 25-2, 16 (m, 1H), 2.14-2.05 (m, 1H), 1.87-1.80 (m, 1H), 1.75-1, 64 (m, 1H), 1.60 (s, 3H), 1.46-1.40 (m, 1H), 1.34 (s, 9H), 1.26-1.15 (m, 2H).

Stage B. rac- (1R, 2S, 5R) -1-Acetam¡do-N- (ferc-but¡l) -2 - ((3,4-d¡h¡dro¡soqu¡nol¡n-2 (1H) -l) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexanecarboxamide

The title compound was prepared from rac- (1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - ((3,4-dihydro ¡Soqu¡nol¡n-2 (1H) -¡l) methyl) -5-v¡n¡lc¡clohexanecarboxam¡da (85 mg, 0.206 mmol), using the procedure described in the preparation Example 26, step B. The crude product was purified by silica gel flash chromatography (DCM / MeOH 100: 1 to 0: 1) to yield 78 mg (70%) of the desired product as a colorless oil. ESI + MS: m / z = 540.7 (M + 1) +, 562.65 (M + Na) +. 1H NMR (700 MHz, chloroform-d) 510.26 (s, 1H), 8.27 (s, 1H), 7.16-7.12 (m, 2H), 7.11-7.08 (m , 1H), 7.05-7.03 (m, 1H), 3.80-3.72 (m, 1H), 3.68-3.59 (m, 1H), 3.62-3.53 (m, 1H), 3.51-3.47 (m, 1H), 3.23-3.18 (m, 1H), 3.03-2.94 (m, 1H), 2.91 (t , J = 5.9 Hz, 2H), 2.69-2.57 (m, 1H), 2.33-2.28 (m, 1H), 2.17-2.10 (m, 1H), 1.83-1.78 (m, 1H), 1.71-1.64 (m, 1H), 1.59 (s, 3H), 1.42-1.37 (m, 1H), 1, 32 (s, 9H), 1.31-1.28 (m, 1H), 1.24 (s, 12H), 1.03-0.94 (m, 2H), 0.91-0.78 ( m, 2H), 0.77-0.69 (m, 1H).

Stage C. Rac- acid dihydrochloride (1R, 2S, 5R) -1-amno-5- (2-boronoethyl) -2 - ((3,4-d¡h¡ dro¡soqu¡nol¡n-2 (1 H) -¡l) methyl) ddohexanecarboxylic

The title compound was prepared from (1R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2 - ((3,4-dihydro¡soqu ¡Nol¡n-2 (1 H) -¡l) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡ l) ethyl) ddohexanecarboxamide (78 mg, 0.145 mmol), using the procedure described in the preparation of Example 26, step C. The crude product was purified by interchangeable chromatography. ionic in DOWEX® and then by preparative HPLC (0.1 - 10% MeCN in water) to provide (after acidification with 6M HCl) the desired product (3.1 mg, 5%) as a white solid. ESI + MS: = 361.4 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 57.46 - 7.14 (m, 4H), 4.63 - 4.54 (m, 1H), 4.43 - 4.24 (m, 1H), 3.89-3.74 (m, 1H), 3.52-3.44 (m, 1H), 3.44-3.05 (m, 4H), 2.29-2.20 ( m, 2H), 1.93-1.83 (m, 3H), 1.79-1.68 (m, 1H), 1.34-1.22 (m, 3H), 1.02-0, 91 (m, 1H), 0.77-0.70 (m, 2H).

Example 36. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-tr Fluoroet¡l) am¡no) methyl) cyclohexanecarboxylic

Stage A. rac- ( 1 R, 2S, 5R) -1-Acetamide-N- (tert-butyl) -2 - (((2,2,2-trifluoroethyl) amine ) methyl) -5-v¡n¡lc¡clohexanecarboxam¡da

The title compound rac- (1R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2 - (((2,2,2-trifluoroethyl) amine ) methyl) -5-v¡n¡lc¡clohexanecarboxam¡da was obtained in the same way as in Example 26, step A, using rac- (1R, 2R, 4R) -2-acetamid -2- (tert-but¡lcarbamo¡l) -4-v¡n¡lc¡clohexane-1-carboxylate (Intermediate 1, 400 mg, 1.18 mmol, 1 equ¡v.), DIBAL -H 1M in DCM (3.66 mL, 3.66 mmol, 3.1 equiv.), Glacial acetic acid (337 ^ L, 5.9 mmol, 5 equiv.) , 2,2,2-trifluoroethyl amine hydrochloride (480 mg, 3.54 mmol, 3 equiv.), sodium trioxy borohydride (1.0 g , 4.72 mmol, 4 equiv.). The residue was purified by silica gel flash chromatography (hexane / AcOEt 2: 1 to 1: 1) to provide the corresponding product as a single diastereoisomer (50 mg, 11% , white solid). ESI + MS: m / z = 378.2 (M + 1) +; ESI-MS: m / z = 376.1 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 59.21 (s, 1H), 8.26 (s, 1H), 5.71 ( ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 4.99-4.91 (m, 2H), 3.57 (t, J = 10.8 Hz, 1H), 3 , 25-3.20 (m, 3H), 3.18-3.07 (m, 1H), 2.79 (d, J = 12.9 Hz, 1H), 2.16 (qd, J = 13 , 3.3, 4.3 Hz, 1H), 2.10 - 2.02 (m, 1H), 1.93 (s, 3H), 1.85 - 1.76 (m, 1H), 1.51 - 1.46 (m, 1H), 1.45-1.39 (m, 1H), 1.32 (s, 8H), 1.20-1.10 (m, 2H).

E cap B. rac - (1 R, 2 S, 5 R) -1 -A ce ta m ¡do -N - (fe rc -but¡ l) -5 - (2 - (4, 4, 5, 5 -te tra met¡l-1, 3, 2 -d ¡o xa bo ro la n -2 -¡l) et¡ l) -2 - (((2, 2, 2 -tr¡fluo roe t¡l ) am ¡no) met¡l) c ¡c lohexanoca rboxam ¡da

The title compound rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl, 3,2- Dioxaborolan-2-¡l) ethyl) -2 - (((2,2,2-tnfluoroetN) amino) metN) cidohexanecarboxamide was obtained in the same way as in Example 26, step B, using rac- (1 R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2 - (((2,2,2-trifluoroethyl) amine) methyl) -5 -vinylcyclohexanecarboxamide (40 mg, 0.11 mmol, 1 equiv.), dppe (2.5 mg, 0.006 mmol, 0.06 equiv.), bisO ^ -cyclooctadiene ^ iiridioO dichloride) (2.1 mg,

0.003 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23 ^ L, 0.16 mmol, 1.5 equiv.) And DCM (2 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 10: 1 to 1: 2) to provide the corresponding product as a single diastereoisomer (40 mg, 56%, white solid). ESI + MS: m / z = 506.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 59.18 (s, 1H), 8.28 (s, 1H), 3.61-3.55 (m, 1H), 3.29-3.17 (m , 2H), 3.17-3.08 (m, 1H), 2.76 (d, J = 12.8 Hz, 1H), 2.08 (qd, J = 13.1.4.3 Hz, 1H), 1.92 (s, 3H), 1.81-1.72 (m, 1H), 1.66-1.57 (m, 1H), 1.49-1.38 (m, 2H) , 1.36-1.31 (m, 1H), 1.31 (s, 9H), 1.23 (s, 12H), 1.03-0.86 (m, 3H), 0.80 (ddd , J = 17.1, 11.0, 6.1 Hz, 1H), 0.72 (ddd, J = 16.0, 11.0, 5.5 Hz, 1H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-tri-fluoroethyl) am No) methyl) cyclohexanecarboxylic.

The title compound rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-trifluoroethyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride was obtained from the same way as in Example 26, step C, using (1R, 2S, 5R) -1-acetamide-N- (fe / 'c-butyl) -5- (2- (4,4, 5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) -2 - (((2,2,2-trifluoroethiO amino ^ ethyl) cyclohexanecarboxamide (30 mg, 0, 06 mmol, 1 equiv.) And 6N HClac (2 mL). The residue was purified by preparative HPLC (0.1 -5% MeCN in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the corresponding product as a single diastereoisomer (0.8 mg, 3%, white solid) ESI + MS: m / z = 309.2 (M-18) +. 1H NMR (700 MHz, Deuterium Oxide) 54.30 - 4 , 22 (m, 1H), 4.15-4.03 (m, 1H), 3.98 (dd, J = 11.0, 5.8 Hz, 1H), 3.38 (d, J = 11 , 0 Hz, 1H), 2.61-2.55 (m, 1H), 2.39-2.32 (m, 1H), 2.19-2.13 (m, 1H), 1.82 - 1.75 (m, 1H), 1.47-1.36 (m, 3H), 1.34-1.27 (m, 1H), 1.17-1.08 (m, 1H), 1, 07-0.99 (m, 1H), 0.86 - 0.80 (m, 2H).

Example 37. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) dihydrochloride am¡no) methyl) cyclohexanecarboxylic

Step A. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) -5-vinylcyclohexane-1-carboxamide

To a solution of ethyl rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexanecarboxylate (Intermediate 1, 317 mg, 0.94 mmol, 1 equiv.) In dry dichloromethane (20 mL) A solution of 1M DIBAL-H in DCM (2.80 mL, 2.80 mmol, 2.98 equiv.) Was added dropwise at -78 ° C under argon. The reaction was stirred at -78 ° C and monitored by TLC (hexane: AcOEt 1: 5). After 1h, the reaction mixture was quenched with glacial acetic acid (268 ^ L, 4.70 mmol, 5 equiv.) And stirred at -78 ° C for 10 min. Then, p-methoxy-N-methylaniline (258 mg, 1.88 mmol, 2 equiv.) Was added dropwise and the cooling bath was removed. After 15 min, sodium triacetoxyborohydride (798 mg, 3.76 mmol, 4 equiv.) Was added portionwise and the resulting mixture was allowed to warm to room temperature and then stirred overnight. The mixture was diluted with dichloromethane and the organic layer was washed with 1N NaOH (10 mL) and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient elution, DCM: MeOH, 1: 0 to 3: 1) to provide the corresponding product rac- (1R, 2S, 5R) -1-acetamido-N- ( tert-butyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) -5-vinylcyclohexanecarboxamide as a single diastereoisomer (yield: 212 mg, 54%, colorless oil). ESI + MS: m / z = 416.50 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 58.99 (s, 1H), 8.31 (s, 1H), 6.90-6.86 (m, 2H), 6.85-6.82 (m , 2H), 5.72 (ddd, 1H, J = 17.1, 10.4, 6.5 Hz), 4.98 (dt, 1H, J = 17.3, 1.5 Hz), 4, 92 (dt, 1H, J = 10.4, 1.7 Hz), 4.14 -4.07 (m, 2H), 3.77 (s, 3H), 3.20 (dt, 1H, J = 13.4, 2.4 Hz), 2.89 (dd, 1H, J = 14.7, 2.35 Hz), 2.80 (s, 3H), 2.18 (qd, 1H, J = 13 , 2.4Hz), 2.14-2.08 (m, 1H), 1.86-1.81 (m, 1H), 1.79-1.73 (m, 4H), 1.53 - 1.47 (m, 1H), 1.36 (s, 9H), 1.18 (qd, 1H, J = 12.9, 4.4 Hz).

Step B. rac- (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) -5- (2- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide

A mixture of dppe (12.2 mg, 0.031 mmol, 0.06 equiv.) And bis (1,5-cyclooctadiene) diiridium (I) dichloride (10.3 mg,

0.015 mmol, 0.03 equiv.) In dichloromethane (5 mL) was purged with argon (bubbling). Subsequently, the separately prepared solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.11 ^ L, 0.76 mmol, 1.5 equiv.) And rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) -5-vinylcyclohexanecarboxamide (212 mg, 0.51 mmol, 1 equiv.) In CH2Cl2 dry (5 mL) was added successively at room temperature. The resulting mixture was stirred at room temperature overnight. The product was concentrated in vacuo and purified by silica gel flash chromatography (gradient elution, hexane / AcoEt 1: 0 to 3: 1) to provide rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl ) cyclohexanecarboxamide (41 mg, 15%, colorless oil). ESI + MS: m / z = 543.95 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 58.94 (s, 1H), 8.34 (s, 1H), 6.88-6.85 (m, 2H), 6.85-6.81 (m , 2H), 4.15 -4.10 (m, 2H), 3.77 (s, 3H), 3.49 (d, 1H,, J = 5.2 Hz), 3.20-3.16 (m, 1H), 2.86 (dd, 1H, J = 14.9, 2.1 Hz), 2.79 (s, 3H), 2.10 (qd,, 1H, J = 13.3, 4.1 Hz), 1.84-1.79 (m, 1H), 1.78-1.72 (m, 4H), 1.48-1.43 (m, 1H), 1.35 (s , 9H), 1.34-1.25 (m, 3H), 1.23 (s, 12H), 0.85-0.78 (m, 2H).

Step C. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride

A mixture of (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) -5- (2- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (41 mg, 0.075 mmol, 1 equiv.) And 6 Nac HCl (15 mL) was heated under reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (gradient elution, 5-50%, MeCN in H2O), acidified with 6N HCl, and lyophilized to provide rac-acid dihydrochloride (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) cyclohexanecarboxylic (4.7 mg, 17%, white solid). ESI + MS: m / z = 365.25 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.60 - 7.56 (m, 2H), 7.25 - 7.21 (m, 2H), 3.95 - 3.88 (m, 4H), 3 , 61 (dd, 1H, J = 10.8, 13.1), 3.34 (s, 3H), 2.27-2.21 (m, 1H), 1.96-1.81 (m, 3H), 1.78-1.71 (m , 1H), 1.71-1.63 (m, 1H), 1.35-1.26 (m, 2H), 1.22-1.18 (m, 1H), 1.18-1.12 (m, 1H), 0.81-0.74 (m, 2H).

Example

Step A. (1R, 2S, 5R) - (+) - 1-Acetamid-N- (tert-butyl) -2 - ((dimethyl) methyl) -5- v¡n¡lc¡clohexanecarboxam¡da

The title compound (1R, 2S, 5R) -1-acetamide-N- (tert-butyl) -2 - ((dimethyl) methyl) -5-v¡n Cyclohexanecarboxamida was obtained in the same way as in Example 26, step A, using (1R, 2R, 4R) -2-acetamid-2- (tert-butycarbamoil) -4- Ethyl vinylclohexane-1-carboxylate (Intermediate 2, 2.5 g, 7.39 mmol, 1 equiv.), 1M DIBAL-H in DCM (22.9 mL,

22.9 mmol, 3.1 equiv.), Glacial acetic acid (2.1 mL, 36.93 mmol, 5 equiv.), 2M di solution metlamine in THF

(7.40 mL, 14.77 mmol, 2 equiv.), Sodium triacetoxyboronhydride (6.26 g, 29.55 mmol, 4 equiv.). The crude product was purified by silica gel flash chromatography (DCM / MeOH, 50: 1 to 10: 1) to provide the corresponding product as a single diastereoisomer (1.69g, 70 %, white solid). ESI + MS: m / z = 324.2 (M + 1) +. [a] D = 114.95 (c = 0.455 in CHCla). 1H NMR (700 MHz, Chloroform-d) 5 10.22 (s, 1H), 8.22 (s, 1H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 4.97 (dt, J = 17.3, 1.5 Hz, 1H), 4.93-4.88 (m, 1H), 3.40 (dd, J = 13.4, 10, 6Hz, 1H), 3.21 (d, J = 13.3Hz, 1H), 2.25 (s, 6H), 2.19-2.06 (m, 2H), 1.99 (d, J = 13.5 Hz, 1H), 1.90 (s, 3H), 1.82-1.78 (m, 1H), 1.56-1.50 (m, 1H), 1.39-1 , 35 (m, 1H), 1.33 (s, 9H), 1.21-1.11 (m, 2H).

Step B. (1R, 2S, 5R) -1-Acetamid-N- (tert-butyl) -2 - ((dimethyl) methyl) -5- (2- ( 4,4,5,5-tetramethyl) -1,3,2-d¡oxaborolan-2-¡l) eth¡l) cyclohexanecarboxamide and acid (2 - ((1R, 3R, 4S) -3-acetamide-3- (tert-butylcarbamo¡l) -4 - ((d¡melam¡no) methyl) cyclohex¡l) eth¡l) boronic.

The title compounds (1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - ((dimethylamine) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cdohexanecarboxamide and acid (2 - ((1 R, 3R, 4S) - (+) - 3-acetam¡do-3- (tert-but¡lcarbamo¡l) -4 - ((dimet¡lam¡no) methyl) c¡dohex¡l) et¡l) boron They were obtained in the same way as in Example 26, step B, using (IR, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - (( d¡methylamno) methyl) -5-v¡n¡lddohexanecarboxam¡da (1.59 g, 4.91 mmol, 1 equ¡v.), dppe (0.12 g, 0.29 mmol, 0.06 equ¡v.), b¡s (1,5-cyclooctadene) dichloride (l) (0.10 g, 0.15 mmol , 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.78 mL, 12.29 mmol, 2.5 equiv.) and DCM (60 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 40: 1 to 5: 1) to provide the corresponding products as diastereoisomers. unique (1.49 g, 68%).

(1R, 2S, 5R) -1-acetamid-N- (tert-butyl) -2 - ((dimethyl) methyl) -5- (2- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) cyclohexanecarboxamida: 0.86g, sticky light yellow solid. ESI + MS: m / z = 452.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 10.21 (s, 1H), 8.26 (s, 1H), 3.45-3.38 (m, 1H), 3.19 (d, J = 13.3 Hz, 1H), 2.24 (s, 6H), 2.15-2.03 (m, 1H), 2.00-1.94 (m, 1H), 1.89 (s, 3H ), 1.86-1.74 (m, 1H), 1.56-1.44 (m, 2H), 1.31 (s, 12H), 1.30-1.24 (m, 2H), 1.23 (s, 9H), 1.22-1.20 (m, 1H), 1.01-0.90 (m, 2H), 0.76 (ddd, J = 47.1, 10.9 , 5.4 Hz, 2H). During purification on silica gel column chromatography, the pinacolboronate ester was partially deprotected to provide a free boronic acid (acid 2 - ((1R, 3R, 4S) -3-acetamide-3- (tert-but¡lcarbamo¡l) -4 - ((d¡melam¡no) methyl) cyclohex¡l ) ethyl) boronic: 0.63g, yellowish foam. [a] D = 48.15 (c = 0.34 in CHCh). ESI + MS: m / z = 370.2 (M + 1) +. 1H NMR (700MHz, Chloroform-d) 510.24 (s, 1H), 8.16 (s, 1H), 4.57-4.54 (m, 1H), 3.46-3.36 (m , 1H), 3.23-3.14 (m, 1H), 2.47-2.30 (m, 1H), 2.24 (s, 6H), 2.15-2.03 (m, 2H ), 1.98 (dt, J = 15.6, 6.6 Hz, 1H), 1.90 (s, 3H), 1.81-1.74 (m, 1H), 1.67-1, 60 (m, 2H), 1.33 (d, J = 7.8Hz, 1H), 1.31 (s, 9H), 1.29-1.25 (m, 2H), 0.99 (dd , J = 14.1, 9.4 Hz, 2H), 0.89-0.70 (m, 1H).

Stage C. Acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimetholamine) methyl) cyclohexanecarboxylic co

The title compound acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamine) methyl) cyclohexanecarboxylic It was obtained in the same way as in Example 26, step C, using acid (2 - ((1R, 3R, 4S) -3-acetamide-3- (tert-butycarbamoil) -4 - ((dimethylamno) methyl) cyclohex¡l) ethyl) boron¡co (0.63g, 1.70 mmol, 1 equ¡v.), HCl 6 Nac (40 mL). The crude product was purified by flash chromatography on a DOWEX® 50WX8 ion exchange resin (eluent, 0.1 N ammonia in water) to provide a desired product as a solid. white (0.43 g, 73%). ESI + m S: m / z = 273.3 (M + 1) +. [a] D = -44.8 (c = 0.125 in H2O). 1H NMR (700 MHz, Deuterium Oxide) 52.87 (dd, J = 13.1, 9.5 Hz, 1H), 2.63 (dd, J = 13.2, 4.7 Hz , 1H), 2.46 (s, 6H), 2.00 (ddd, J = 13.0, 3.5, 1.9 Hz, 1H), 1.81-1.72 (m, 2H), 1.59 (dddt, J = 16.5, 12.8, 10.4, 3.4 Hz, 2H), 1.54-1.48 (m, 1H), 1.22 (ddt, J = 11 , 5, 6.9, 2.9 Hz, 2H), 1.01 (t, J = 12.6 Hz, 1H), 0.88 (qd, J = 12.9, 4.2 Hz, 1H) , 0.72-0.67 (m, 2H).

Acid dihydrochloride (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethyl) methyl) c Clohexanecarboxylic.

Treatment of acid (1R, 2S, 5R) -1-amino-5- (2-boronoet¡l) -2 - ((d¡met¡lam¡no) metal) c¡ Chlohexanecarboxylic with HClac 6N and subsequent liquefying yielded the hydrochloride salt as a white solid in quantitative yield. ESI + MS: m / z = 273.3 (M + 1) +. [a] D = 6.98 (c = 0.345 in H2O). 1H NMR (700 MHz, Deuterium Oxide) 53.27 (dd, J = 13.3, 2.6 Hz, 1H), 3.23-3.16 (m, 1H), 2.90 (s, 3H), 2.84 (s, 3H), 2.25 (d, J = 14.9 Hz, 1H), 2.13 (s, 1H), 1.87 (d, J = 12, 8Hz, 2H), 1.82-1.75 (m, 1H), 1.71-1.62 (m, 1H), 1.33-1.25 (m, 3H), 0.98-0 , 90 (m, 1H), 0.72 (dd, J = 9.1,7.3 Hz, 2H).

Example 39. D ih id ro c lo ru ro de l ác ido (1 R, 2 S, 5 R) -1 -am in o -5 - (2 -bo ro noe til) -2 - (( me tila m in o) me til) c ic lo hexanoca rb ox flic o

Step A. (1 R, 2S, 5R) -1-Acetamido-2 - ((benzyl (methyl) amino) methyl) -N- (fe / 'c-butyl) -5-vinylcyclohexanecarboxamide

The title compound (1R, 2S, 5R) -1-acetamido-2 - ((benzyl (methyl) amino) methyl) -N- (te / -c-butyl) -5-vinylcyclohexanecarboxamide was obtained in the same way as in Example 26, step A, using ethyl (1R, 2R, 4R) -2-acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 2, 400 mg, 1, 18 mmol, 1 equiv.), 1M DIBAL-H in DCM (3.66 mL,

3.66 mmol, 3.1 equiv.), Glacial acetic acid (0.34 mL, 5.90 mmol, 5 equiv.), N-benzylmethylamine (0.38 mL, 2.95 mmol, 2.5 equiv. ), sodium triacetoxyborohydride (1.0 g, 4.72 mmol, 4 equiv.) and DCM (30 mL). The residue was purified by silica gel flash chromatography (DCM: MeOH 20: 1) to provide the corresponding product as a single diastereoisomer (418 mg, 84%, yellow oil). ESI + MS: m / z = 400.3 (M + 1) + 1H NMR (700 MHz, Chloroform- d) 59.92 (s, 1H), 8.22 (s, 1H), 7.37-7 , 18 (m, 5H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.04-4.85 (m, 2H), 3.59 (dd , J = 13.5, 9.8 Hz, 2H), 3.29 (dd, J = 88.2, 13.0 Hz, 2H), 2.21 (s, 3H), 2.19-2, 13 (m, 2H), 2.12-2.03 (m, 1H), 1.85 (s, 3H), 1.82-1.76 (m, 1H), 1.64-1.57 ( m, 1H), 1.43-1.38 (m, 1H), 1.29 (s, 9H), 1.19-1.11 (m, 2H).

Step B. (1R, 2S, 5R) -1-acetamido-2 - ((bendl (methyl) amino) methyl) -N- (tert-butyl) -5- (2- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexanecarboxamide

The title compound (1R, 2S, 5R) -1-acetamido-2 - ((bendl (methyl) amino) methyl) -N- (tert-butyl) -5- (2- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexanecarboxamide was obtained in the same way as in Example 26, step B, using the compound (1R, 2S, 5R) -1-acetamido-2- ((bendl (methyl) amino) methyl) -N- (tert-butyl) -5-vinylcyclohexanecarboxamide (405 mg,

1.01 mmol, 1 equiv.), Dppe (24.1 mg, 0.0606 mmol, 0.06 equiv.), Bis (1,5-cidooctadiene) diiridium (I) dichloride (20.4 mg, 0 , 0303 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3 mL, 2.02 mmol, 2 equiv.) And DCM (6 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 40: 1 to 20: 1) to provide the corresponding product as a single diastereoisomer (387 mg, 72%, yellow oil). ESI + MS: m / z = 528.45 (M + 1) +, 1H NMR (700 MHz, Chloroform-d) 59.94 (s, 1H), 8.19 (s, 1H), 7.37 - 7.18 (m, 5H), 3.64-3.56 (m, 2H), 3.37-3.18 (m, 2H), 2.20 (s, 3H), 2.17-2, 05 (m, 2H), 1.84 (s, 3H), 1.71-1.66 (m, 4H), 1.41-1.29 (m, 2H), 1.28 (s, 9H) , 1.23 (s, 12H), 1.03-0.90 (m, 2H), 0.85-0.68 (m, 2H).

Step C. (1R, 2S, 5R) -1-amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

The title compound (1R, 2S, 5R) -1-amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride was obtained in the same way as in Example 26, step C, using (1R, 2S, 5R) -1-acetamido-2 - ((bendl (methyl) amino) methyl) -N- (tert-butyl) -5- (2- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (145 mg, 0.275 mmol, 1 equiv.) And 6 Nac HCl (10 mL). The residue was purified by preparative HPLC (5-30% MeCN in water) to provide (after acidification with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (51.2 mg, 53%, white solid). ESI + MS: m / z = 349.25 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 57.74 - 7.26 (m, 5H), 4.35 (dd, J = 76.1, 13.0 Hz, 2H), 3.33 - 3.11 (m, 2H), 2.87 (s, 3H), 2.37-2.16 (m, 1H), 2.10-1.83 (m, 2H), 1.82-1.37 (m , 3H), 1.36-1.15 (m, 3H), 1.00-0.81 (m, 1H), 0.76-0.63 (m, 2H).

Step D. (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) acid dihydrochloride (1R, 2S, 5R) -1 acid dihydrochloride was dissolved -amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexanecarboxylic (45 mg, 0.13 mmol, 1 equiv.) in 2 mL absolute EtOH and purged with argon. Then, 8 mg of 10% wet Pd / C was added and the resulting mixture was stirred under a hydrogen atmosphere (balloon) for 3 h. Then, a mixture was filtered through the Celite pad (washed several times with EtOHabs) and the solvent was evaporated. The residue was dissolved in water and lyophilized to provide the product as a single diastereoisomer (21.7 mg, 65%, white solid). ESI + MS: m / z = 259.15 (M + 1) +. [a] D = -39.8 (c = 0.125 in H2O).

1H NMR (700 MHz, Deuterium Oxide) 53.48 (m, 1H), 3.31-3.25 (m, 1H), 2.94 (s, 3H), 2.53-2.43 (m , 1H), 2.33-2.25 (s, 1H), 2.17-2.08 (m, 3H), 2.05-1.95 (m, 1H), 1.94-1.85 (m, 1H), 1.56-1.48 (m, 3H), 1.21-1.13 (m, 1H), 1.00-0.92 (m, 2H).

Example 40. Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride

Step A. rac- (1R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((phenylamino) methyl) -5-vinylcyclohexane-1-carboxamide

To a solution of ethyl rac- (1 ^, 2 ^, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcidohexanecarboxylate (Intermediate 1, 100 mg, 0.30 mmol, 1 equiv.) In dry dichloromethane (10 mL), 1M DIBAL-H in DCM (0.92 mL,

0.92 mmol, 3.1 equiv.) At -78 ° C under argon. Then aniline (54 ^ L, 0.60 mmol, 2 equiv.) And glacial acetic acid (85 ^ L, 1.48 mmol, 5 equiv.) Were added. The reaction was stirred for 30 min at room temperature and sodium triacetoxyborohydride (254 mg, 1.2 mmol, 4 equiv.) Was added. The reaction mixture was diluted with DCM (10 mL), washed with 1M NaOH (2 x 10 mL), brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by silica gel flash chromatography (gradient elution, DCM / MeOH 1: 0 to 50: 1) to provide (1 R, 2S, 5R) -1-acetamido-N- (fe / 'c- butyl) -2 - ((phenylamino) methyl) -5-vinylcyclohexanecarboxamide as a single diastereoisomer (137 mg, 100% yield, white solid). ESI + MS: m / z = 385.50 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 8.13-8.06 (m, 1H), 7.98 (s, 1H), 7.24-7.20 (m, 2H), 6.82 ( t, 1H, J = 7.3 Hz), 6.71 (d, 2H, J = 7.8 Hz), 5.73 (ddd, 1H, J = 10.6, 6.4,

3.9 Hz), 4.99 (dt, 1H, J = 17.3, 1.5 Hz), 4.94 (dt, 1H, J = 10.4, 1.4 Hz), 4.01-3, 88 (m, 1H), 3.15-3.06 (m, 2H), 2.19-2.09 (m, 2H), 1.89-1.83 (m, 1H), 1.83-1, 76 (m, 4H), 1.73-1.67 (m, 1H), 1.36 (s, 9H), 1.33-1.18 (m, 3H).

Step B. rac- (1R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((methyl (phenyl) amino) methyl) -5-vinylcyclohexane-1-carboxamide

To a solution of rac- (1R, 2S, 5R) -1-acetamido-N- (fe / 'c-butyl) -2 - ((phenylamino) methyl) -5-vinylcyclohexanecarboxamide (222 mg, 0.60 mmol, 1 equiv.) In dry dichloromethane (10 mL), formalin (231 ^ L, 3.00 mmol, 5 equiv.) And glacial acetic acid (34 ^ L, 0.60 mmol, 1 equiv.) Were added. The reaction mixture was stirred for 30 min at room temperature and sodium triacetoxyborohydride (381 mg, 1.80 mmol, 3 equiv.) Was added and stirred for 3 days. The reaction mixture was then quenched with 5% NaHCO3 (10 mL) and the layers were separated. The aqueous layer was washed with dichloromethane (3 x 10 mL) and the combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide the corresponding product as a Single diastereoisomer (yield 264 mg, 23%, white solid). ESI + MS: m / z = 385.50 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 58.30 (s, 1H), 8.29 (s, 1H),

7.28 - 7.24 (m, 2H), 6.89 - 6.83 (m, 3H), 5.73 (ddd, 1H, J = 7.3, 17.1.6.5 Hz), 4.99 (dt, 1H, J = 17.3, 1.5 Hz), 4.93 (dt, 1H, J = 10.4, 1.4 Hz), 4.22 (dd, 1H, J = 15.1, 10.2 Hz), 3.17 (dt, 1H, J = 13.3, 2.3 Hz), 3.04 (dd, 1H, J = 15.1, 3.0 Hz), 2.89

(s, 3H), 2.18 (dq, 1H, J = 13.3, 4.3 Hz), 2.16-2.08 (m, 1H), 1.90-1.83 (m, 2H ), 1.69 (s, 3H), 1.58-1.52 (m, 2H), 1.38 (s, 9H), 1.30-1.17 (m, 2H).

Step C. rac- (1R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((methyl (phenyl) amino) methyl) -5- (2- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexane-1-carboxamide

A mixture of dppe (13.1 mg, 0.033 mmol, 0.06 equiv.) And bis (1,5-cyclooctadiene) diiridium (I) dichloride (11.1 mg, 0.016 mmol, 0.03 equiv.) In dichloromethane (5 mL) was purged with argon (bubbling). Subsequently, the separately prepared solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.12 ^ L, 0.83 mmol, 1.5 equiv.) And (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((methyl (phenyl) amino) methyl) -5-vinylcyclohexanecarboxamide (211 mg, 0.55 mmol, 1 equiv.) In dry CH2Cl2 (5 mL) are added successively at room temperature. The resulting mixture was stirred at room temperature overnight. After concentration, the crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 1: 0 to 4: 1) to provide rac- (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2 - ((methyl (phenyl) amino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (161 mg, 57%, yellow liquid). ESI + MS: m / z = 514.70 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 58.29 (s, 1H), 7.24 (s, 1H), 7.27-7.23 (m, 2H), 6.88-6.81 (m , 3H), 4.23 (dd, 1H, J = 15.1, 10.8 Hz), 3.14 (d, 1H, J = 13.4 Hz), 3.01 (dd, 1H, J = 15.1, 3.1 Hz), 2.88 (s, 3H), 2.08 (dq, 1H, J = 8.6, 4.5 Hz), 1.92-1.80 (m, 2H ), 1.66 (s, 3H), 1.55-1.49 (m, 1H), 1.36 (s, 9H), 1.35-1.28 (m, 3H), 1.23 ( s, 12H), 1.05 (dd, 1H, J = 12.1, 13.3 Hz), 0.98 (dq, 1H, J = 13.1,4.6 Hz), 0.85-0 , 78 (m, 1H), 0.76-0.70

(m, 1H).

Step D. Ac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride

A mixture of rac- (1R, 2S, 5R) -1-acetamido-N- (fe / 'c-butyl) -2 - ((methyl (phenyl) amino) methyl) -5- (2- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (160 mg, 0.19 mmol, 1 equiv.) And 6N Helac (15 mL) was refluxed for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with 6N HCl and subsequent lyophilization) a product desired as a single diastereoisomer (22.9 mg, 18%, white solid). ESI + MS: m / z = 335.50 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.27 - 7.68 (m, 2H), 7.68 - 7.64 (m, 1H), 7.63 - 7.60 (m, 2H), 3 , 97 (dd, 1H, J = 13.6, 2.5 Hz), 3.65 (dd, 1H, J = 10.6, 13.4 Hz), 2.36 (s, 3H), 2, 26-2.21 (m, 1H), 1.96-1.82 (m, 3H), 1.79-1.72 (m, 1H), 1.72-1.66 (m, 1H), 1.34-1.26 (m, 2H), 1.14 (t, 1H, J = 12.6Hz), 0.82-0.72 (m, 3H).

Comparative Example 41. 1-Amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) -4,4-dimethylcyclohexane-1-carboxylic acid dihydrochloride.

Step A. Ethyl 5,5-Dimethyl-2-oxocyclohex-3-enocarboxylate

The title compound 5,5-dimethyl-2-oxoxydohex-3-enocarboxylate ethyl was obtained in the same way as in step A from the synthesis of intermediate 1 using 4,4-dimethylcyclohexenone (2.6 mL, 20.13 mmol, 1 equiv.), Ethyl chloroform (2.3 mL, 24.15 mmol, 1.2 equiv.), N-BuLi (2.5 M in hexane) (12.1 mL, 30, 19 mmol, 1.5 equiv.), Diisopropylamine (4.2 mL, 30.19 mmol, 1.5 equiv.), 4-dimethylaminopyridine (0.12 g, 1 mmol, 0.05 equiv.), Dry THF (45mL). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 200: 1 to 10: 1) to provide the corresponding product ethyl 5,5-dimethyl-2-oxocyclohex-3-enocarboxylate ( 1.28g, 32%, yellow oil). ESI + MS: m / z = 197.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 56.10 - 6.03 (m, 1H), 5.86 (d, J = 9.8 Hz, 1H), 4.25

(q, J = 7.1 Hz, 2H), 1.35-1.31 (m, 3H), 1.29 (t, J = 7, 11.3H), 1.23 (s, 3H), 1.22 (s, 3H).

Step B. Ethyl 5,5-Dimethyl-2-oxo-4-vinylcyclohexanecarboxylate

The title compound 5,5-dimethyl-2-oxo-4-vinylcyclohexanecarboxylate ethyl ester as a mixture of diastereoisomers was obtained in the same way as in step B from the synthesis of intermediate 1, using 5,5-dimethyl Ethyl -2-oxocyclohex-3-enocarboxylate (1.0 g, 5.30 mmol, 1 equiv.), Vinyl magnesium bromide (1 M in THF) (18.5 mL, 18.50 mmol, 3.5equiv. ), HMPA (3.7 mL, 21.20 mmol), CuBr x Me2S (0.16 g, 0.80 mmol, 0.15 equiv.), And TMSCl (3.4 mL, 26.5 mmol, 5 equiv.), dry THF (23 mL + 11mL). The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 200: 1 to 20: 1) to provide the corresponding product ethyl 5,5-dimethyl-2-oxo-4-vinylcyclohexanecarboxylate as a mixture of diastereoisomers dr = 3: 2 (0.1 g, 8%, yellow oil). ESI + MS: m / z = 225.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 55.76 (ddd, J = 17.0, 10.4, 8.4 Hz, 1H), 5.23 - 4.92 (m, 2H), 4.24 (dtq, J = 10.8, 7.4, 3.8 Hz, 2H), 2.39, 2.36 [(2d, J = 5.7 Hz, 1H, two diastereoisomers)], 2.26 2 , 22 (m, 1H), 2.17-2.10

(m, 2H), 2.07-2.04 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.30 (dd, J = 16.9, 7.1 Hz, 1H), 0.99 (s, 3H), 0.87 (s, 3H).

Step C. 2-Acetam¡do-2- (tert-but¡lcarbamo¡l) -5,5-d¡me¡l-4-v¡n¡lc¡clohexanecarboxylate ethyl

The title compound 2-acetamide-2- (tert-butylcarbamoil) -5,5-dimethyl-4-v¡nlc¡clohexanecarboxylate ethyl ester was obtained from the same way as in stage C from the synthesis of intermediate 1 using a 5,5-d¡met¡l-2-oxo-4-v¡n¡lc¡clohexanecarbox Ethyl oxide (dr = 3: 2) (0.1 g, 0.45 mmol, 1 equiv.), Ammonium acetate (0.14 g, 1.78 mmol,

4 equiv.), Tert-butylsocyanide (0.1 mL, 0.89 mmol, 2 equiv.), And 2,2,2-trifluoroethanol (1.6 mL) as a solvent. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 50: 1 to 1: 1) to provide the corresponding product 2-acetamine. do-2- (tert-but¡lcarbamo¡l) -5,5-d¡met¡l-4-v¡n¡lc¡clohexanecarboxylate of ethyl as a mixture of two d¡astereo¡somers ( dr = 1: 1) (0.66 g, 40%, white solid). ESI + MS: m / z = 367.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 58.11 (s, 1H), 7.49 (s, 1H), 5.78 -5.59 (m, 1H), 5.12-4.90 (m , 2H), 4.24, 4.16 [(2dq, J = 10.8, 7.1 Hz;

J = 10.9, 7.1 Hz, 2H, two diastereoisomers)], 3.00 (dd, J = 14.4, 3.0 Hz, 1H), 2.54 (dd, J = 13.0, 4.2 Hz, 1H), 2.01 (s, 3H), 1.99-1.94 (m, 1H), 1.90-1.84 (m, 1H), 1.83 - 1.71 (m, 1H), 1.50 (s, 3H), 1.31 (s, 9H), 1.19-1.08 (m, 1H), 0.93 (s, 3H), 0.85 (s, 3H).

Step D. 1-Acetamid-N- (tert-butyl) -2 - ((dimethyl) methyl) -4,4-di-methyl-5-v¡ n¡lc¡clohexanecarboxam¡da

The title compounds 1-acetamide-N- (tert-butyl) -2 - ((dimethylamine) methyl) -4,4-dimethyl-5-v N¡lcyclohexanecarboxam¡da was obtained in the same way as in Example 26, step A, using 2-acetamide-2- (tert-but¡lcarbamo¡l) -5,5-d¡ ethyl methyl-4-v¡n¡lc¡clohexanecarboxylate (dr = 1: 1), (0.6 g, 0.17 mmol, 1 equ¡v.), DIBAL-H 1M in DCM (0.5 mL, 0.52 mmol,

3.1 equiv.), Glacial acetic acid (0.05 mL, 0.83 mmol, 5 equiv), dimethyl amine (2N in THF) ( 0.17 mL, 0.33 mmol,

2 equiv.), Sodium tetraacetoxyboronhydride (0.14 g, 0.07 mmol, 4 equiv.), Dry DCM (5 mL). The residue was purified by silica gel flash chromatography (elution gradient DCM: MeOH 100: 1 to 10: 1) to provide the corresponding products 1-acetamide-N- ( tert-but¡l) -2 - ((d¡met¡lam¡no) methyl) -4,4-d¡me¡l-5-v¡n¡lc¡clohexanecarboxam¡da as a mixture of d Astereoisomers (dr. = 1: 1) (34 mg, 58%, colorless oil). ESI + MS: m / z = 352.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 510.14 (s, 1H), 8.12 (s, 1H), 5.68 (ddd, J = 17.1, 10.4, 8.5 Hz, 1H ), 5.03-4.93 (m, 2H), 3.49-3.35 (m, 1H), 2.97-2.92 [(m, 1H, two diasteriosomers)], 2.28 (s, 3H), 2.21-2.19 (m, 1H), 2.14-2.06 (m, 1H), 1.99-1.95 (m, 1H),

1.92 (s, 3H), 1.88-1.78 (m, 1H), 1.62-1.59 (m, 1H), 1.53 (s, 3H), 1.34 (s, 9H), 1.02, 1.00 [(2d, J = 3.9 Hz, J = 4.0 Hz, 1H two dastereomers)], 0.91 (s, 3H), 0.89 (s, 3H).

Step E. 1 -Acetamide-N- (tert-butyl) -2 - ((dimethyl) methyl) -4,4-dimethyl-5- (2 - (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamide

The title compound was obtained in the same manner as in Example 26, step B, using 1-acetaminophen-N- (tert-butyl) -2 - ((dimethylamine) methyl l) -4,4-d¡met¡l-5-v¡n¡lc¡clohexanecarboxam¡da (dr = 1: 1), (0.034g, 0.1 mmol, 1 equ¡v.), dppe ( 2.5 mg,

0.006 mmol, 0.06 equiv.), B¡s (1,5-cyclooctadene) d¡¡r¡d¡o (I) chloride (2mg, 0.003. Mmol, 0, 03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.018 mL, 0.013 mmol, 1.3 eq). The crude product was used for the next step without any additional purification (134 mg of crude mixture, approx. 11%, yellow oil). ESI + MS: m / z = 480.4 (M + 1) +.

Step F. 1-Amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) -4,4-dimethylcidohexane-1-carboxylic acid dihydrochloride

The title compound was obtained in the same way as in Example 26, step C, using 1-acetamido-N- (tert-butyl) -2 - ((dimethylamino) methyl) -4,4-dimethyl-5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexanecarboxamide (crude, 134 mg, 0.28 mmol, 1 equiv.), 6N HClac (1.5 mL ). The residue was purified by preparative HPLC (0.1-1% MeCN in water) and then by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidify with 6N HCl and subsequent lyophilization) 1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) -4,4-dimethylcyclohexane-1-carboxylic acid dihydrochloride as a mixture of two diastereoisomers

(dr = 1: 1) (2.5 mg, 2%, white solid). ESI + MS: m / z = 301.2 (M + 1) +. ESI-MS: m / z = 299.1 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 83.27 (d, J = 15.5 Hz, 1H), 3.18 (t, J = 12.7 Hz, 1H), 2.90 (s, 3H) , 2.82 (s, 3H), 2.39-2.21 (m, 1H), 2.20-2.19 (m, 1H), 2.17-2.10 (m, 1H), 1 , 82-1.73 (m, 1H), 1.71-1.62 (m, 1H), 1.48 (td, J = 10.1, 9.0, 5.6 Hz, 3H),

1.28-1.17 (m, 1H), 0.95 (s, 3H), 0.81 (s, 3H), 0.63-0.53 (m, 1H).

Example 42. (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) cyclohexanecarboxylic acid dihydrochloride

Step A. tert-butyl (1- (2-Oxocyclohex-3-en-1-yl) ethyl) carbamate.

To a solution of diisopropylamine (11.76 mL, 83.22 mmol) in dry THF (91 mL) was added dropwise a solution of n-BuLi in THF (2.5M, 33.3 mL, 83.22 mmol ) at -78 ° C under argon. The reaction mixture was warmed to room temperature, stirred for 15 min and cooled to -78 ° C. A 2-cycloheksen-1-one (4 g,

41.61 mmol) and the mixture was stirred for 1h at this temperature. Then, a solution of tere-butyl- (1-tosylethyl) carbamate (12.46 g, 41.61 mmol) in THF (53 mL) was added dropwise and the reaction was stirred for 1.5 h at -78 ° C. The mixture was then quenched with saturated NH4Cl (150 mL) and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane / AcEt (20: 1-2: 1) to provide the product (3.2 g, 32%) as a colorless oil. ESI + MS: m / z = 240.15 (M + 1) +, 140.15 (M-Boc + 1) +. 1H NMR (700 MHz, chloroform-d) 57.00 - 6.95 (m, 1H), 6.01 -5.96 (m, 1H), 5.70 -5.65 (m, 1H), 3 .86 - 3.79

(m, 1H), 2.59-2.49 (m, 1H), 2.49-2.38 (m, 2H), 2.02-1.9 (m, 1H), 1.88 (tdd , J = 13.1, 10.6, 5.1 Hz, 1H), 1.45 (s, 9H), 1.16 (d, J = 6.9 Hz, 3H).

Step B. tere-butyl (1 - ((4R) -2-Üxo-4-vinylcyclohexyl) ethyl) carbamate

Rh (cod) BF4 (178 mg, 0.437 mmol), (R) -BINAP (272 mg,

0.437 mmol), and potassium vinyl trifluoroborate (3.55 g, 26.49 mmol). The flask was flushed with argon several times and degassed 96% EtHH (105 mL) and trimethylamine (5.54 mL, 39.74 mmol) were added. After stirring the resulting mixture for 10 min at room temperature, tere-butyl (1- (2-oxocyclohex-3-en-1-yl) ethyl) carbamate (3.17 g, 13.25 mmol) was added and the reaction mixture was stirred at room temperature for 6 days. The EtHH was evaporated. The residue was diluted with ethyl acetate (100 mL), and 0.5 M aqueous HCl (30 mL) and brine (30 mL) were washed, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane / AcÜEt (15: 1 to 5: 1) to yield the product as a mixture of diastereoisomers (overall yield: 430 mg, 12%). ESI + MS: m / z = 290.15 (M + Na) +, 168.15 (M-Boc + 1) +, 212.15 (M-56 + 1) +. The first diastereoisomer was isolated as a colorless oil (320mg, 9%). [a] D = 6.6 (c = 0.250 in CHCh).

1H NMR (700 MHz, chloroform-d) 55.79 (ddd, J = 16.9, 10.4, 6.2 Hz, 1H), 5.27 (s, 1H), 5.07 - 4.98 (m, 2H), 3.87-3.73 (m, 1H), 2.58-2.51 (m, 1H), 2.50-2.40 (m, 2H), 2.25-2 , 14 (m, 1H), 2.12-2.05 (m, 1H), 2.02-1.97 (m, 1H), 1.60-1.56 (m, 2H), 1.45 (s , 9H), 1.25 (d, J = 6.9 Hz, 3H). The second diastereoisomer was isolated as a colorless oil (110 mg, 3%). 1H NMR (700 MHz, chloroform-d) 55.87 -5.73 (m, 1H), 5.23 (s, 1H), 5.09-4.97 (m, 2H), 3.88-3 , 72 (m, 1H), 2.56-2.35 (m, 3H), 2.31-2.14 (m, 1H), 2.14-1.95 (m, 1H), 1.95-1 , 76 (m, 2H), 1.73-1.63 (m, 1H), 1.44 (s, 9H), 1.22 (d, J = 6.9Hz, 3H).

Step C. (1 - ((1S, 2R, 4R) -2-Acetamido-2- (tere-butylcarbamoyl) -4-vinylcyclohexyl) ethyl) tere-butyl carbamate

To the stirred solution of tere-butyl (1 - ((4R) -2-oxo-4-vinylcyclohexyl) ethyl) carbamate (550 mg, 2.45 mmol) and ammonium acetate (0.76 g, 9.87 mmol) in 2,2,2-trifluoroethanol (10 mL), tere-butyl isocyanide (0.55 mL,

4.94 mmol) via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, 2,2,2-trifluoroethanol was evaporated and the residue was diluted with ethyl acetate (40 mL) and washed with water (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography using hexane / AcÜEt (30: 1 to 1: 1) to provide a mixture of diastereoisomers (overall yield: 495 mg, 49%). ESI + MS: m / z = 410.25 (M + 1) +, 354.25 (M-56 + 1) +, 310.2 (M-Boc + 1) +. The first diastereoisomer was isolated as a colorless oil

(190 mg, 19%) and was used in the next step. 1H NMR (700 MHz, chloroform-d) 57.87 (s, 1H), 6.33 (s, 1H), 5.72 (ddd, J = 17.1, 10.5, 6.4 Hz, 1H ), 5.02 - 4.92 (m, 2H), 4.77 (d, J = 10.5 Hz, 1H), 3.44 - 3.38 (m, 1H), 2.53-2, 37 (m, 1H), 2.09 (s, 3H), 1.94-1.84 (m, 2H), 1.84-1.75 (m, 2H), 1.45 (s, 9H) , 1.36 (s, 9H), 1.30 (d, J = 6.5 Hz, 3H), 1.22 (d, J = 6.8 Hz, 1H), 1.19-1.12 ( m, 2H).

Step D. (1R, 2S, 5R) -1-Acetamido-2- (1-aminoethyl) -N- (tere-butyl) -5-vinylcyclohexanecarboxamide hydrochloride

x HCI

To tert-butyl (1 - ((1S, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl) ethyl) carbamate (190 mg, 0.464 mmol) was added 4M HCl in dioxane ( 2 mL) and the solution was stirred at room temperature until the substrate was consumed (TLC monitoring). Then, it was concentrated in vacuo and 160 mg (99%) of crude product was obtained as a colorless oil and was used in the next step. ESI + m S: m / z = 310.15 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 58.56 (s, 2H), 7.41 (s, 1H), 6.81 (s, 1H), 5.74 (ddd, J = 16.6, 10 , 8, 5.8 Hz, 1H), 5.17-4.93 (m, 2H), 3.43-3.27 (m, 1H), 2.80-2.42 (m, 2H), 2.31 (s, 3H), 2.03-1.73 (m, 4H), 1.54-1.49 (m, 2H), 1.41 (s, 9H), 1.34-1, 12 (m, 3H).

Step E. (1R, 2S, 5R) -1-Acetamido-N- (tert-butyl) -2- (1- (dimethylamino) ethyl) -5-vinylcyclohexanecarboxamide

(1R, 2S, 5R) -1-Acetamido-2- (1-aminoethyl) -N- (ferf-butyl) -5-vinylcyclohexanecarboxamide hydrochloride (160 mg, 0.46 mmol), formalin (36% , 0.14 mL, 1.85 mmol) in 1,2-dichloroethane (1.5 mL). The mixture was stirred at room temperature for 1h. Sodium triacetoxyborohydride (0.39 g, 6.2 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was then diluted with DCM (50 mL) and washed with 5% NaHCO3 (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (DCM / MeOH 50: 1 to 5: 1)) to yield 74 mg (38%) of the desired product as a colorless oil. ESI + MS: m / z = 338.05 (M + 1) +. 1H Rm N (700 MHz, chloroform-d) 57.85 (s, 1H), 7.25 (s, 1H), 5.76 (ddd, J = 17.1, 10.4, 6.4 Hz, 1H), 5.07-4.88 (m, 2H), 2.75-2.66 (m, 1H), 2.26 (s, 6H), 2.17-2.10 (m, 1H) , 2.05 (s, 3H), 1.85-1.65 (m, 3H), 1.62-1.44 (m, 2H), 1.35 (s, 9H), 1.29-1 , 21 (m, 1H), 1.01 (d, J = 7.1 Hz, 3H).

Step F. (2 - ((1R, 3R, 4S) -3-acetamido-3- (tert-butylcarbamoyl) -4 - ((1- (dimethylamino) ethyl) cyclohexyl) ethyl) boronic acid

A mixture of dppe (4.9 mg, 0.012 mmol) and bis (1,5-cyclooctadiene) diiridium (I) dichloride (4.1 mg, 0.0061 mmol) in dry dichloromethane (2 mL) was purged with argon . Then, the solution of (1R, 2S, 5R) -1-acetamido-N- (tert-butyl) -2- (1- (dimethylamino) ethyl) -5-vinylcyclohexanecarboxamide (69 mg, 0.204 mmol ) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (136 µl, 0.94 mmol) in DCM (2 mL) (argon purged). The reaction mixture was stirred at room temperature overnight. After that time, the reaction mixture was diluted with DCM (20 mL), washed with 5% NaHCO3 (2 x 20 mL). The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography, on silica gel (CH2Cl2 / MeOH 20: 1 to MeOH) to provide the product (35 mg, 45%) as a colorless oil. ESI + MS: 384.2 (M + 1) +. 1H NMR (700 MHz, chloroform-d) 53.71-3.55 (m, 1H), 2.87-2.78 (m, 1H), 2.76-2.60 (m, 1H), 2 , 22 (s, 6H), 2.07-2.01 (m, 5H), 1.86-1.72 (m, 2H), 1.34 (s, 9H), 1.24-2.12 (m, 3H), 0.98-0.91 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H).

Step G. (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) cyclohexanecarboxylic acid dihydrochloride

A mixture of (2 - ((1R, 3R, 4S) -3-acetamido-3- (tert-butylcarbamoyl) -4- (1- (dimethylamino) ethyl) cyclohexyl) ethyl) boronic acid (30 mg, 0.078 mmol and 6N HClac (5 mL) was heated under reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® and then by preparative HPLC (0.1 MeCN - 1% in water) to provide (after acidification with 6M HCl and subsequent lyophilization) the desired product (11 mg, 38%) as a white solid ESI + MS: 287.1 (M + 1) +. 1H NMR (700 MHz, deuterium oxide) 53.31 (q, J = 6.9 Hz, 1H), 2.78 (d, J = 14.3 Hz, 6H), 2.55 (dd, J = 13, 6, 3.4Hz, 1H), 2.04 (d, J = 14.4Hz, 1H), 1.94-1.84 (m, 2H), 1.74-1.67 (m, 1H ), 1.59-1.49 (m, 1H), 1.36-1.26 (m, 3H), 1.25 (d, J = 7.0 Hz, 3H), 1.16-1, 08 (m, 1H), 0.74-0.65 (m, 2H).

E jem p lo 43. D ih id ro c lo ru ro de l ác ido (2 - ((1 R, 3 R, 4 S) -3 -am in o -4 - ((d im e tila m in o ) me til) -3 - (me to x ica rb on il) c ic lo hex il) e til) bo ró n ico

Step A. (2 - ((1R, 3R, 4S) -3-amino-4 - ((dimethylamino) methyl) -3- (methoxycarbonyl) cidohexyl) ethyl) boronic acid dihydrochloride

To a solution of (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) acid hexanecarboxylic acid (27 mg,

0.1 mmol, 1eq) in a toluene / methanol mixture (3: 2, 0.45 mL) a solution of (diazomethyl) trimethylsilane (2N in diethyl ether) (0.075 mL, 1.5 eq) was added dropwise ) at room temperature. The resulting mixture was stirred for 5 hours and then concentrated in vacuo. The crude product was purified by silica gel flash column chromatography using DCM / MeOH (100: 1 to 20: 1) as eluent. The fractions with the desired product were collected, concentrated, and the residue was dissolved in 6M HClac. The resulting solution was subjected to preparative HPLC (MeCN at

0.1-1% in water) to yield 9.5 mg (26%) of acid dihydrochloride (2 - ((1R, 3R, 4S) -3-amino-4 - ((dimethylamino) methyl) -3- (methoxycarbonyl) cyclohexyl) ethyl) boronic as a white solid. ESI + m S: m / z = 287.1 (M + 1) +. It is I-MS: m / z = 299.1 (M-1) -.

1H NMR (700 MHz, D2O) 53.69 (s, 3H), 3.17 (dd, J = 13.3, 2.4 Hz, 1H), 3.09-3.02 (m, 1H), 2.79 (s, 3H), 2.73 (s, 3H), 2.16 (ddd, J = 13.3, 3.1.2.0 Hz, 1H), 2.13-2.08 ( m, 1H), 1.83-1.73 (m, 2H), 1.68-1.60 (m, 1H), 1.48-1.40 (m, 1H), 1.26 (t, J = 12.9 Hz, 1H), 1.23-1.13 (m, 2H), 0.89-0.80 (m, 1H), 0.60 (t, J = 8.0 Hz, 2H ).

General synthetic route for Examples 44 and 45

Comparative Example 44. (1R, 2S, 5R) -1-amino-2 - ((dimethylamino) methyl) -5- (2 - ((3aR, 4R, 6R, 7aS) -3a, 5.5- trimethylhexahydro-4,6-methanobenzo [d] [1,3,2] dioxaborol-2-yl) ethyl) cyclohexane-1-carboxylic

A mixture of (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) acid dihydrochloride (0.03 g, 0.087 mmol, 1 eq), (1R , 2R, 3S, 5R) - (-) - 2,3-pinanediol (22 mg, 0.13 mmol) in acetonitrile (1 mL) was heated under reflux for 1 hour. After that time, an additional amount of pinenediol (7 mg, 0.043 mmol) was added and heating was continued for one hour. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether (3 x 3 mL) to provide 27 mg. (65%) of the corresponding product as a white solid. ESI + MS: m / z = 407.4 (M + 1) +. Is I-MS: m / z = 405.3 (M-1) -. 1H NMR (700 MHz, DMSO) 58.90 (bs, 2H), 4.28 (dd, J = 8.7, 1, 9 Hz, 1H), 3.52-3.38 (m, 1H), 2.96-2.87 (m, 1H), 2.75 (s, 6H), 2.31-2.25 (m , 1H), 2.17 (ddd, J = 10.5, 6.2, 4.1 Hz, 2H), 2.11 (bd, J = 13.1 Hz, 1H), 1.95 (t, J = 5.5 Hz, 1H), 1.88-1.83 (m, 1H), 1.76 (bd, J = 12.4 Hz, 1H), 1.71-1.67 (m, 1H ), 1.66-1.58 (m, 2H), 1.32-1.29 (m, 4H), 1.28-1.22 (m, 5H), 0.98 (d, J = 10 , 7Hz, 1H), 0.87-0.80 (m, 4H), 0.75-0.66 (m, 2H).

Comparative Example 45. (1R, 2S, 5R) -1-amino-2- (pyrrolidin-1-ylmethyl) -5- (2 - ((3aR, 4R, 6R, 7as) -3a, 5.5 -trimethylhexahydro-4,6-methaneobenzo [d] [1,3,2] dioxaborol-2-yl) ethyl) cyclohexanecarboxylic

A mixture of rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexanecarboxylic acid dihydrochloride (0.03 g, 0.08 mmol, 1 equiv.), (1R, 2R, 3S, 5R) - (-) - 2,3-pinanediol (0.02g, 0.12mmol, 1.5equiv.) in acetonitrile (3mL) was sonicated for 30 min at 35 ° C. After that time, the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether (3 x 3 mL). The white solid was filtered and sonicated with acetone (1 mL) for 1 min at 35 ° C. The product separated (0.04g, 98%) as a white solid. ESI + MS: m / z = 433.5 (M + 1) +. ESI-MS: m / z = 431.3 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 54.36 (d, J = 7.2 Hz, 1H), 3.66 (dp, J = 11.3, 4.1 Hz, 2H), 3.37-3.20 (m, 2H), 3.07 (dt, J = 11.4, 8.1 Hz, 1H), 2.96 (dt, J = 11.4, 8.4 Hz, 1H), 2.43-2.27 (m, 1H), 2.23-2.16 (m, 2H), 2.15-2.01 (m, 3H), 2.01-1.83 (m, 6H), 1.81-1.72 (m, 2H), 1.72-1.65 (m, 1H), 1.33 (d , J = 1.3 Hz, 2H), 1.28 (dd, J = 37.2, 6.5 Hz, 2H), 1.24-1.17 (m, 5H), 0.94 (dd, J = 11.0, 4.2 Hz, 2H), 0.81 (t, J = 7.9 Hz, 2H), 0.77 (s, 3H).

Example 46. (5R) -1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid dihydrochloride

Step A. Ethyl 2 - ((1R, 4R) -2-Oxo-4-vinylcyclohexyl) acetate and ethyl 2 - ((1S, 4R) -2-oxo-4-vinylcyclohexyl) acetate

The three neck round bottom flask was charged with [Rh (cod) 2] BF4 (0.78 g, 1.92 mmol, 0.03 equiv.), (R) -BINAP (1.31 g, 2, 11 mmol, 0.033 equiv.) And potassium vinyl trifluoroborate salt (17.1 g, 0.128 mol, 2.0 equiv.). The reaction flask was flushed with argon several times and a degassed mixture of dioxane: H2O (150: 75 mL) was added along with triethylamine (26.7 mL, 0.192 mole, 3.0 equiv.). After stirring the reaction mixture for 10 min at room temperature, ethyl 2- (2-oxocyclohex-3-en-1-yl) acetate (11.7 g, 0.064 mol, 1 equiv.) Was added. The reaction mixture was stirred for 4 days at room temperature under argon. The solvents were evaporated in vacuo and the crude reaction mixture was partitioned between water and EtOAc. The aqueous layer was washed with EtOAc. The combined organic layers were washed with 0.5M HClac and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 30: 1) to provide the product as a mixture of diastereoisomers, dr = 1: 1, (1.6 g, 12%, yellow liquid). [a] D = -3.12 (c = 1.0 in CHCla). 1H NMR (700 MHz, Chloroform-d) 5 5.85 -5.62 [(m, 1H) two diastereoisomers], 5.14 - 4.91 [(m, 2H, two diastereoisomers)], 4.12 - 4.07 [(m, 2H, two diastereoisomers)], 2.85-2.78 (m, 1H), 2.76-2.68 (m, 1H), 2.51-2.37 (m, 2H), 2.27-2.17 (m, 1H), 2.16-2.09 (m, 2H), 1.95-1.89 (m, 1H), 1.64-1.55 ( m, 1H), 1.42 (qd, J = 13.1, 3.5 Hz, 1H), 1.24-1.21 [(m, 3H, two diastereoisomers)].

Step B. 2- (4R) -2-Acetamido-2- (-butylcarbamoyl) -4-vinylcyclohexyl) ethyl acetate

To the stirred solution of ethyl 2 - ((4R) -2-oxo-4-vinylcyclohexyl) acetate (dr = 1: 1, 1.6 g, 7.6 mmol, 1 equiv.) And ammonium acetate (2 , 34 g, 0.0305 mol, 4 equiv.) In 2,2,2-trifluoroethanol (4 mL), tert-butylisocyanide (1.71 mL, 0.0152 mol, 2 equiv.) Was added via syringe and the resulting mixture was stirred at room temperature for 24 hours. After that time, the solvent was evaporated and the crude material was partitioned between ethyl acetate (50 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and washed with brine.

(10 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 2: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 1: 1 (0.7 g, 25 %, white solid). [a] D = -2.92 (c = 1.0 in CHCla). ESI + MS: m / z = first diastereoisomer 353.35 (M + 1) +, 375.35 (M + Na) +, second diastereoisomer 353.4 (M + 1) +, 375.40 (M + Na) +, 1H NMR (700 MHz, Chloroform-d) 58.07, 7.87 [2s, 1H, two diastereoisomers)], 7.60, 7.46 [(s, 1h, two diastereoisomers)], 5.76 -5.62 [(m, 1H two diastereoisomers)] 5.05-4.84 [(m, 2H two diastereoisomers)], 4.23-4.06 (m, 2H), 3.14-2.96 (m, 2H), 2.67, 2.53 [(dd, J = 16.8, 6.9 Hz, dd, J = 16.8, 3.3 Hz, 1H, two diastereoisomers), 2.43 (dd, J = 17.9, 3.5 Hz, 1H), 2.29-2.13 (m, 1H), 2.10, 2.00 [(2s, 3H, two diastereoisomers)], 1, 93-1.85 (m, 1H), 1.81-1.73 (m, 1H), 1.67-1.57 (m, 1H), 1.33, 1.32 [(2s, 9H, two diastereoisomers)], 1.29-1.25 (m, 3H), 1.24-1.10 (m, 2H).

Step C. (5R) -1-Acetamido-N- (tert-butyl) -2- (2- (pyrrolidin-1-yl) ethyl) -5-vinylcyclohexanecarboxamide

The title compound (5R) -1-acetamido-N- (tert-butyl) -2- (2- (pyrrolidin-1-yl) ethyl) -5-vinylcyclohexanecarboxamide was obtained in the same way as in Example 26, Step A, using ethyl 2- (4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl) acetate (700 mg, 2.0 mmol, 1 equiv.), 1M DIBAL-H in DCM ( 6.2 mL, 6.2 mmol, 3.1 equiv.), Glacial acetic acid (0.57 mL, 10 mmol, 5 equiv.), Pyrrolidine (0.33 mL, 4.0 mmol, 2.0 equiv .), sodium triacetoxyborohydride (1.7 g, 8.0 mmol, 4 equiv.) and DCM (12 mL). The residue was purified by silica gel flash chromatography (DCM: MeOH 20: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 1: 3 (180 mg, 25%, light yellow oil). [a] D = 32.59 (c = 1.0 in CHCb). ESI + MS: m / z = first diastereoisomer 364.4 (m 1) +, second diastereoisomer 364.45 (M + 1) +, 1H Rm N (700 MHz, Chloroform-d) 5 5.92 -5.54 [(m, 1H, two diastereoisomers)],

5.13 - 4.76 [(m, 2H, two diastereoisomers)], 3.18, 3.07 [(d, J = 12.8 Hz, d, J = 14.0 Hz, 1H, two diastereoisomers) ],

2.86-2.53 (m, 4H), 2.28-2.19 (m, 2H), 2.15-1.83 (m, 8H), 1.70-1.53 (m, 4H ), 1.51-1.40 (m, 1H), 1.33, 1.32 [(2s, 9H, two diastereoisomers)], 1.29-1.20 (m, 1H), 1.16 - 1.03 (m, 2H).

E cap D. (5 R) -1 -ace ta m ¡do -N - (fe / 'c -but¡l) -2 - (2 - (p ¡rro l¡d ¡n -1 -¡l) et¡l) -5 - (2 - (4, 4, 5, 5 -te trametal) -1, 3, 2 -d ¡oxa bo ro la n -2 -il) e til) c id ohexanoca rb oxam id a

The title compound (5R) -1-acetamide-N- (fe / 'c-but¡l) -2- (2- (p¡rrol¡d¡n-1-¡l) eth¡l) -5- (2- (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) c¡dohexanecarboxamida was obtained from the same manner as in Example 26, step B, using (5R) -1-acetamide-N- (fe / 'c-butyl) -2- (2- (p¡rrol¡d¡n-1- ¡L) eth¡l) -5-v¡n¡lc¡clohexanecarboxam¡da (178 mg, 0.49 mmol, 1 equ¡v.), Dppe (11.7 mg, 0.0294 mmol, 0.06 equ¡v.), b¡s (1,5-cyclooctadene) dichloride (I) (9.8 mg, 0.0147 mmol, 0.03 equ ¡V.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.14 mL, 0.98 mmol, 2 equiv.) And DCM (4 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 20: 1 to 9: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 1: 3 (50 mg, 21%, light yellow oil). [a] D = 4.23

(c = 1.0 in CHCh). ESI + MS: m / z = first d¡astereo¡somer 492.6 (M + 1) +, second d¡astereo¡somer 492.55 (M + 1) +, 1H NMR (700 MHz, Chloroform-d) 53.08 (d, J = 13.5 Hz, 1H), 2.99-2.82 (m, 4H), 2.33-2.21 (m, 2H), 2.14-1.92 ( m, 10H), 1.81-1.63 (m, 3H), 1.61-1.48 (m, 3H), 1.41-1.35 (m, 1H), 1.30.1, 29 [(2s, 9H, two diastereoisomers)], 1.22, 1.21 [(2s, 12H, two diastereoisomers)], 0.90 - 0.82 (m, 1H) , 0.80-0.64 (m, 2H).

Stage E. Acid dihydrochloride (5R) -1-amino-5- (2-boronoet¡l) -2- (2- (p¡rrol¡d¡n-1-¡l ) ethyl) cyclohexanecarboxylic

The title compound acid dihydrochloride (5R) -1-amino-5- (2-boronoethyl) -2- (2- (p¡rrol¡d¡n-1-¡ l) ethyl) cyclohexanecarboxylic was obtained in the same manner as in Example 26, step C, using (5R) -1-acetamid-N- (fe / 'c-butyl ) -2- (2- (p¡rrol¡d¡n-1-¡l) eth¡l) -5- (2- (4,4,5,5-tetramethyl-1,3,2- d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamida (50 mg, 0.1 mmol, 1 equiv.) and 6 N HClac (10 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC. It goes (0.1 - 10% MeCN in water) to provide (after acidification with 6N HCl and subsequent bleaching) the product as diastereomers separable (7.4 mg, 23%, white solids).

First diastereoisomer (1.2 mg), ESI + MS: m / z = 313.40 (M + 1) +. [a] D = -42.2 (c = 0.125 in H2O). 1H NMR (700 MHz, Deuterium Oxide) 53.72-3.60 (m, 2H), 3.37-3.22 (m, 2H), 3.14-3.02 (m, 2H), 2.21-2.07 (m, 3H), 2.06-1.90 (m, 5H), 1.74-1.63 (m, 2H), 1.61-1.52 ( m, 1H), 1.45-1.34 (m, 3H), 1.33-1.22 (m, 1H), 1.16-1.04 (mi, 1H), 0.86-0, 76 (m, 2H). Second d¡astereo¡somer (6.2 mg), ESI + MS: m / z = 313.35 (M + 1) +, 1H NMR (700 MHz, Deuterium oxide) 5 3.73 - 3.65 (m, 2H), 3.41 (td, J = 12.3, 4.7 Hz, 1H), 3.23 (td, J = 12.2, 4.9 Hz, 1H), 3 , 16-3.06 (m, 2H), 2.29 (ddd, J = 13.2, 3.3, 1.8 Hz, 1H), 2.22-2.12 (m, 2H), 2 , 10-1.98 (m, 3H), 1.96-1.81 (m, 3H), 1.79-1.66 (m, 2H), 1.65-1.56 (m, 1H) 1.42 - 1.28

(m, 3H), 1.02-0.90 (m, 1H), 0.86-0.75 (m, 2H).

Example 47. Acid dihydrochloride (5R) -1-amino-5- (2-boronoethyl) -2- (2- (dimethylamine) ethyl) cyclohexanecarboxylic

Step A. 2 - ((1 ^, 4 ^) - 2-Oxo-4-vinylcidohexyl) ethyl acetate and 2 - ((1S, 4 ^) - 2-Oxo-4-vinylcidohexyl) acetate

The title compound 2 - ((1R, 4R) -2-oxo-4-v¡nilddohex¡l) ethyl acetate and 2 - ((1S, 4R) -2-oxo-4-v¡nilddohex¡l) Ethyl acetate was obtained in the same manner as in Example 46, step A, using ethyl 2- (2-oxocyclohex-3-en-1-yl) acetate (7.05 g, 0.0387 mol, 1 equiv .), [Rh (cod) 2] BF4 (0.47 g, 1.16 mmol, 0.03 equiv.), (R) -BINAP (0.79 g, 1.28 mmol, 0.033 equiv.) And potassium vinyl trifluoroborate salt (10.4 g, 0.0774 mole, 2.0 equiv.), triethylamine (16.3 mL, 0.116 mole, 3.0 equiv.) and EtOHabs (312 mL) as a solvent. The crude product was purified by silica gel flash chromatography (Hex: AcOEt, 30: 1) to provide the desired product as a mixture of diastereoisomers, dr = 1: 1, (1.6 g, 19%, yellow liquid) . [a] D = 38.9 (c = 0.250 in CHCla). 1H NMR (700 MHz, Chloroform-d) 55.79-5.67 (m, 1H, two diastereoisomers)], 5.07-4.92 (m, 2H, two diastereoisomers)], 4.13-4, 05 (m, 2H, two diastereoisomers)], 2.85-2.76 (m, 1H), 2.75-2.67 (m, 1H), 2.52-2.36 (m, 2H), 2.27-2.16 (m, 1H), 2.15-2.08 (m, 2H), 1.95-1.87 (m, 1H), 1.64-1.54 (m, 1H ), 1.46-1.34 (m, 1H), 1.24-1.17 (m, 3H, two diastereoisomers)].

Step B. 2- (4R) -2-Acetam¡do-2- (¡tert-but¡lcarbamo¡l) -4-v¡n¡lddohex¡l) ethyl acetate

The title compound 2- (4R) -2-acetamid-2- (tert-butylcarbamol) -4-v¡n¡lddohex¡l) ethyl acetate was obtained in the same way as in the Example 46, step B, using ethyl 2 - ((1 R ^ R ^ -oxo ^ -vinylcyclohexiOacetate and 2 - ((1 S, 4R) - 2-oxo-4-v¡n¡lc¡dohex¡l) Ethyl acetate (1.6 g, 7.6 mmol, 1 equiv.), ammonium acetate (2.34 g, 0.0305 mol, 4 equiv.), tert-butylisocyanide (1.71 mL, 0.0152 moles, 2 equiv.) and 2,2,2-trifluoroethanol (5 mL) as a solvent The residue was purified by flash chromatography on silica gel (gradient elution, hexane / AcOEt 10: 1 to 7: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 1: 1 (1.5 g, 52%, white solid). ESI + MS: m / z = first diastereoisomer 353.45 (M + 1) +, second diastereoisomer 353.45 (M + 1) +. [A] D = 31.9 (c = 0.250 in CHCb).

1H NMR (700 MHz, Chloroform-d) 8.05, 7.87 [(2s, 1H, two diastereoisomers)], 7.60, 7.46 [(2s, 1H, two diastereoisomers)], 5.75 -5.60 [(m, 1H, two diastereoisomers)], 5.03-4.83 [(m, 2H, two diastereoisomers)], 4.27 -4.03 (m, 2H), 3.17 - 2.90 (m, 2H), 2.66, 2.52 [(dd, J = 16.8, 6.9 Hz; dd, J = 16.8, 3.4 Hz, 1H, two diastereoisomers)] , 2.45-2.39 (m, 1H), 2.25-2.13 (m, 1H), 2.09, 2.00 [(2s, 3H, two diastereoisomers)], 1.94-1 , 85 (m, 1H), 1.81-1.72 (m, 1H), 1.66-1.56 (m, 1H), 1.32, 1.31 [(2s, 9H, two diastereoisomers) ], 1.29-1.24 (m, 3H), 1.23-1.12 (m, 2H).

Step C. (5R) -1-Acetamid-N- (tert-butyl) -2- (2- (dimethyl) ethyl) -5-v¡n¡lddohexanecarboxam¡ gives

The title compound (5 ^) - 1-acetamido-N- (tert-butyl) -2- (2- (dimethylamino) ethyl) -5-vinylcidohexanecarboxamide was obtained in the same way as in Example 26, step A, using ethyl 2- (4 ^) - 2-acetamide-2- (tert-butycarbamoyl) -4-vinylcidohexyl) acetate (1.5 g, 4.26 mmol, 1 equiv.), DlBAL -H 1M in d Cm (13.2 mL, 0.0132 moles, 3.1 equiv.), Glacial acetic acid (1.2 mL, 0.0213 moles, 5 equiv.), 2N dimethyl amine in THF (5 , 32 mL, 0.0106 mmol, 2.5 equiv.), Sodium triacetoxyborohydride (3.6 g, 0.017 mmol, 4 equiv.) And DCM (15 mL). The crude product was purified by silica gel flash chromatography (gradient elution DCM: MeOH 10: 1 to 5: 1) to provide the corresponding product as a mixture of diastereoisomers, dr. = 1: 4 (480 mg, 34%, pale yellow oil). ESI + MS: m / z = first diastereoisomer 338.45 (M + 1) +, second diastereoisomer 338.45 (M + 1) +. [a] D = 53.2 (c = 0.250 in CHCla). 1H NMR (700 MHz, Chloroform-d) 5.80 -5.65 [(m, 1H, two diastereoisomers)], 5.10-4.83 [(m, 2H, two diastereoisomers)], 3.22 , 3.11 (dt, J = 13.4, 2.5 Hz; dt, J = 13.5, 3.1 Hz, 1H, two diastereoisomers)], 2.42-2.34 (m, 1H) , 2.30, 2.27 (2s, 6H, two diastereoisomers)], 2.23 (td, J = 13.1.4.2 Hz, 1H), 2.17-2.02 (m, 2H) , 2.00, 1.94 (2s, 3H, two diastereoisomers)], 1.84-1.73 (m, 1H), 1.68-1.56 (m, 2H), 1.55-1, 47 (m, 1H), 1.33, 1.32 [(2s, 9H, two diastereoisomers)], 1.31-1.15 (m, 1H), 1.15-1.03 (m, 2H) .

Step D. (5R) -1-Acetamid-N- (fe / 'c-butyl) -2- (2- (dimethyl) ethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide

The title compound (5R) -1-acetamid-N- (fe / 'c-butyl) -2- (2- (dimethyl) ethyl) -5- (2 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide was obtained in the same way as in Example 26, step B, using (5R) -1 -acetamid-N- (fe / 'c-butil) -2- (2- (dimethylamine) ethyl) -5-vnllddohexanecarboxamide (470 mg, 1.39 mmol, 1 equiv.), Dppe (33.0 mg, 0.0834 mmol, 0.06 equiv.), BisO ^ -cyclooctadiene ^ iiridium dichloride) (28 mg, 0.0417 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4 mL, 2.78 mmol, 2 equiv.) and DCM (6 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeoH 20: 1 to 9: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 1: 3 (340 mg, 52 %, pale yellow oil). ESI + MS: m / z = first diastereoisomer 466.65 (M + 1) +, second diastereoisomer 466.6 (M + 1) +. [a] D = 51.8 (c = 0.250 in CHCla). 1H NMR (700 MHz, Chloroform-d) 53.16, 3.00 (d, J = 13.3 Hz; d, J = 8.5 Hz, 1H, two diastereoisomers)], 2.50-2.40 (m, 2H), 2.36, 2.33 (2s, 6H two diastereoisomers)], 2.28-2.17 (m, 2H), 2.14-2.02 (m, 2H), 1, 98, 1.96 (2s, 3H, two diastereoisomers)], 1.82-1.70 (m, 1H), 1.67-1.53 (m, 1H), 1.30, 1.29 (2s , 9H two diastereoisomers)], 1.22, 1.21 (2s, 12H two diastereoisomers)], 1.17-1.07 (m, 1H), 0.96-0.81 (m, 4h), 0 , 81-0.66 (m, 2H).

Step E. (5R) -1-amino-5- (2-boronoethyl) -2- (2- (dimethyl) ethyl) ddohexanecarboxylic acid dihydrochloride

The title compounds (5R) -1-amino-5- (2-boronoethyl) -2- (2- (dimethylamino-thiOcyclohexanecarboxylic acid dihydrochloride) were obtained in the same manner as in Example 26, step C, using (5R ) -i-acetamide-N- (fe / 'c-butyl) -2- (2- (dimethyl) ethyl) -5- (2- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-iOeti-cyclohexanecarboxamide (330 mg, 0.65 mmol, 1 equiv.) And 6N HClac (10 mL). The residue was purified by flash chromatography on a DOWEX ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the product as diastereoisomers (19.1 mg, white solid). A single diastereoisomer (16.2 mg, 8%, white solid) separated. ESI + MS: m / z = single isolated diastereoisomer 287.35 (M +1) +, 1H NMR (700 MHz, Deuterium Oxide) 53.35 (td, J = 12.4, 4.8 Hz, 1H), 3.18 (td, J = 12.3, 4.9 Hz, 1H), 2.92 (s, 3H), 2.91 (s, 3H), 2.31 (ddd, J = 13.2, 3.4, 1.8 H z, 1H), 2.07 (tdd, J = 12.5, 4.9, 2.2 Hz, 1H), 1.94-1.86 (m, 2H), 1.86-1.74 ( m, 2H), 1.71 (qd, J = 12.8, 3.3 Hz, 1H), 1.66-1.57 (m, 1H), 1.40-1.34 (m, 3H) , 0.96 (qd, J = 12.9, 3.6 Hz, 1H), 0.84-0.78 (m, 2H).

Example 48. 1,2-Diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

Step A. Ethyl 2 - (((Benzyloxy) carbonyl) amino) hex-5-enoate

To a solution of ethyl 2-aminohex-5-enoate (4 g, 25 mmol, 1 equiv., Prepared from N- (diphenylmethylene) glycine ethyl ester using a method from the literature, WO 2014/009509) in THF-H2O (35 mL - 35 mL) was added potassium carbonate (6.9 g, 50 mmol, 2 equiv.). The mixture was cooled to 0 ° C and N- (benzyloxycarbonyloxy) succinimide (6.35 g, 25 mmol, 1 equiv.) Was added. The reaction mixture was stirred at room temperature overnight. The aqueous layer was separated and washed with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (petroleum ether / AcOEt, 20: 1 to 8: 1) to provide the corresponding product (7.15 g, 96%, colorless oil). ESI + MS: m / z = 314.3 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 57.43 - 7.31 (m, 5H), 5.81 (td, J = 16.8, 6.6 Hz, 1H), 5.32 (d, J = 7.6 Hz, 1H), 5.13 (s, 2H), 5.04 (dd, J = 31.1, 13.6 Hz, 2H), 4.40 (q, J = 7.6 Hz , 1H), 4.22 (q, J = 7.0 Hz, 2H), 2.13 (qt, J = 14.6, 6.9 Hz, 2H), 1.97 (dq, J = 14, 2, 6.2 Hz, 1H), 1.78 (dq, J = 14.0, 8.2 Hz, 1H), 1.32-1.28 (m, 3H).

Step B. 2 - (((benzyloxy) carbonyl) amino) hex-5-enoic acid

To a solution of ethyl 2- (((benzyloxy) carbonyl) amino) hex-5-enoate (7.15 g, 24 mimols, 1 equiv.) In ethanol (50 mL) was added 1N NaOHac (50 mL) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated in vacuo. The aqueous layer was acidified to pH = 2 with 2N HClac. and extracted with ethyl acetate three times. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the corresponding product (5.9 g, 91%, white solid). ESI + MS: m / z = 286.25 (M + Na) +; ESI-MS: m / z = 262.1 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 67.40 - 7.30 (m, 5H), 5.79 (dt, J = 16.7, 8.3 Hz, 1H), 5.27 (d, J = 8.2 Hz, 1H), 5.19 -5.09 (m, 2H), 5.04 (dd, J = 32.4, 13.6 Hz, 2H), 4.44 (q, J = 7.7 Hz, 1H), 2.16 (q, J = 7.2 Hz, 2H), 2.01 (dq, J = 13.2, 7.7 Hz, 1H), 1.80 (dq, J = 14.7, 7.7 Hz, 1H).

Step C. Benzyl (1- (Methoxy (methyl) amino) -1-oxohex-5-en-2-yl) carbamate

To a solution of 2 - (((benzyloxy) carbonyl) amino) hex-5-enoic acid (5.9 g, 22 mmol, 1 equiv.) In dichloromethane (50 mL) was added W, W-diisopropylethylamine (8, 19 mL, 47 mmol, 2.1 equiv.), W, 0-dimethylhydroxylamine hydrochloride (2.3 g,

24 mmol, 1.05 equiv.) And HATU (8.95 g, 24 mmol, 1.05 equiv.). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with 1N NaOHac, 1N HClac, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 10: 1 to 4: 1) to provide the corresponding product (6.7 g, 98%, white solid). ESI + MS: m / z = 307.35 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 67.40 - 7.28 (m, 5H), 5.79 (td, J = 16.9, 6.6 Hz, 1H), 5.45 (d, J = 8.6 Hz, 1H), 5.17-5.02 (m, 3H), 4.99 (d, J = 10.2 Hz, 1H), 4.76 (s, 1H), 3.77 (s, 3H), 3.21 (s, 3H), 2.19-2.08 (m, 2H), 1.88-1.77 (m, 1H), 1.71-1.63 (m , 1 HOUR) .

Step D. Benzyl (3-Oxoocta-1,7-dien-4-yl) carbamate

To a solution of benzyl (1- (methoxy (methyl) amino) -1-oxohex-5-en-2-yl) carbamate (6.6 g, 22 mmol, 1 equiv.) In dry THF (30 mL) under Ar at -78 ° C 1M vinylmagnesium bromide in THF (75 mL, 75 mmol, 3.5 equiv.) was added. The reaction mixture was slowly warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with 2N HClac and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 30: 1 to 8: 1) to provide the corresponding product (670 mg, 9%, colorless oil). ESI + MS: m / z = 296.3 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 67.40 - 7.29 (m, 5H), 6.48 (dd, J = 17.5, 10.4 Hz, 1H), 6.40 (d, J = 17.4 Hz, 1H), 5.91 (d, J = 10.4 Hz, 1H), 5.83 -5.74 (m, 1H), 5.57 (d, J = 7.1 Hz , 1H), 5.11 (s, 2H), 5.02 (dd, J = 27.7, 13.6 Hz, 2H), 4.77-4.70 (m, 1H), 2.17 - 2.08 (m, 1H), 2.07-1.92 (m, 2H), 1.70-1.61 (m, 1H).

Step E. Benzyl (2-Oxocyclohex-3-en-1-yl) carbamate

To a solution of benzyl (3-oxoocta-1,7-dien-4-yl) carbamate (670 mg, 2.45 mmol, 1 equiv.) In dry dichloromethane (120 mL) under Ar was added Grubbs Catalyst, 2nd Generation (104 mg, 0.12 mmol, 0.05 equiv.). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 15: 1 to 3: 1) to provide the corresponding product (520 mg, 86%, white solid). ESI + MS: m / z = 246.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 57.39 - 7.30 (m, 5H), 7.01 - 6.96 (m, 1H), 6.08 (dd, J = 10.0, 2, 4 Hz, 1H), 5.77 (s, 1H), 5.12 (s, 2H), 4.35-4.24 (m, 1H), 2.64 (dd, J = 49.9, 11 , 6Hz, 2H), 2.48 (dt, J = 19.5, 4.7Hz, 1H), 1.80 (qd, J = 12.5, 5.0Hz, 1H).

Step F. Benzyl (2-Oxo-4-vinylcyclohexyl) carbamate

The title compound (2-oxo-4-vinylcyclohexyl) benzyl carbamate was obtained in the same way as in step B from the synthesis of intermediate 1, using (2-oxocyclohex-3-en-1-yl) Benzyl carbamate (500 mg, 2.04 mmol, 1 equiv.), 1M vinylmagnesium bromide in Th F (5.1 mL, 5.1 mmol, 2.5 equiv.), HMPA (1.4 mL, 8 , 16 mmol, 4 equiv.), Copper (I) bromide dimethyl sulfide complex (63 mg, 0.31 mmol, 0.15 equiv.), Trimethylsilyl chloride (1.3 mL, 10.2 mmol,

5 equiv.) And THF (13 mL). The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 15: 1 to 4: 1) to provide the corresponding product as a mixture of diastereoisomers, dr. = 1: 1, (170 mg, 30%, colorless oil). ESI + MS: m / z = 274.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 57.40 - 7.29 (m, 5H), 5.81 -5.76 (m, 1H), 5.75 -5.71 (m, 1H), 5 , 17-4.97 (m, 4H), 4.31-4.15 (m, 1H), 3.02-2.63 [(m, 1H, two diastereoisomers)], 2.57 (ddd, J = 13.0, 4.0, 2.4 Hz, 1H), 2.49-2.41 (m, 1H), 2.31-2.07 [(m, 1H, two diastereoisomers)], 1, 97-1.84 [(m, 1H, two diastereoisomers)], 1.74-1.57 [(m, 1H, two diastereoisomers)], 1.46-1.41 (m, 1H).

Step G. Benzyl (2-Acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl) carbamate

The title compound (2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl) benzyl carbamate was obtained in the same way as in step C from the synthesis of intermediate 1, using (2-oxo-4 -vinylcyclohexyl) benzyl carbamate

(170 mg, 0.62 mmol, 1 equiv.), Ammonium acetate (192 mg, 2.50 mmol, 4 equiv.), Tert-butylisocyanide (140 ^ L, 1.24 mmol, 2 equiv.) And 2 , 2,2-trifluoroethanol (3 mL) as a solvent. The residue was purified by silica gel flash chromatography (hexane / AcOEt 15: 1 to 2: 1) to provide the corresponding product as a mixture of separable diastereoisomers. Overall yield: 47%.

First diastereoisomer (A): (80 mg, colorless oil); ESI + MS: m / z = 416.2 (M + 1) +. 1H NMR (700MHz, Chloroform) 58.39 (s, 1H), 7.39 - 7.29 (m, 5H), 6.98 (s, 1H), 6.08 (d, J = 9.8 Hz, 1H), 5.71 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 5.17 -5.03 (m, 2H), 5.01 - 4.91 ( m, 2H), 3.93-3.49 (m, 1H), 3.24-2.73 (m, 1H), 2.30-2.19 (m, 1H), 2.06-1, 99 (m, 1H), 1.93 (s, 3H), 1.87-1.77 (m, 2H), 1.32 (s, 9H), 1.25-1.15 (m, 2H) .

Second diastereoisomer (B): (40 mg, white solid); ESI + MS: m / z = 416.2 (M + 1) +. 1H NMR (700MHz, Chloroform) 57.76 (s, 1H), 7.56 (s, 1H), 7.38-7.30 (m, 5H), 6.15 (d, J = 7.0 Hz, 1H), 5.74-5.67 (m, 1H), 5.12-5.05 (m, 2H), 5.02-4.92 (m, 2H), 3.65 (ddd, J = 12.8, 7.1, 3.8 Hz, 1H), 2.81 (dt, J = 14.0, 2.7 Hz, 1H), 2.45 (qd, J = 14.7, 13.9, 5.0 Hz, 1H), 2.11-2.05 (m, 1H), 2.05 (s, 3H), 1.91-1.78 (m, 2H), 1.29 (s, 9H), 1.28-1.20 (m, 2H).

Step H. (2-Acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) carbamate benzyl

The title compound (2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) carbamate Benzyl was obtained in the same way as in Example 26, step B, using benzyl (2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexyl) carbamate (diastereoisomer A, 70 mg, 0.17 mmol, 1 equiv.), Dppe (4.1 mg, 0.010 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (3.4 mg, 0.005 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32 ^ L, 0.25 mmol, 1.5 equiv.) And DCM (3 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 15: 1 to 2: 1) to provide the corresponding product as a single diastereoisomer A (70 mg, 76%, colorless oil). ESI + MS: m / z = 544.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 58.40 (s, 1H), 7.38 - 7.28 (m, 5H), 6.91 (s, 1H), 6.12 (d, J = 9 , 6 Hz, 1H), 5.18-5.00 (m, 2H), 3.83-3.51 (m, 1H), 3.20-2.70 (m, 1H), 2.23 - 2.12 (m, 1H), 1.91 (s, 3H), 1.83-1.73 (m, 2H), 1.37-1.30 (m, 2H), 1.30 (s, 9H), 1.23 (s, 12H), 1.07-0.94 (m, 2H), 0.82-0.76 (m, 1H), 0.75-0.67 (m, 2H) .

The second diastereoisomer was obtained in the same way starting from: benzyl (2-acetamido-2- (fercbutylcarbamoyl) -4-vinylcyclohexyl) carbamate (diastereoisomer B, 40 mg, 0.096 mmol, 1 equiv.), Dppe (2 , 3 mg, 0.006 mmol,

0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (2.0 mg, 0.003 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane (21 ^ L, 0.14 mmol, 1.5 equiv.) And DCM (2 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 15: 1 to 2: 1) to provide the corresponding product as a single diastereoisomer.

(35 mg, 67%, colorless oil). ESI + MS: m / z = 544.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.48 (s, 1H), 7.46 (s, 1H), 7.38 - 7.28 (m, 5H), 6.30 (d, J = 7 , 1Hz, 1H), 5.08 (s, 2H), 3.70-3.61 (m, 1H), 2.69 (d, J = 14.0Hz, 1H), 2.29 (qd , J = 13.3, 3.8 Hz, 1H), 2.02 (s, 3H), 1.88-1.75 (m, 3H), 1.38-1.32 (m, 2H), 1.28 (s, 9H), 1.23 (s, 12H), 1.18-1.10 (m, 1H), 1.04-0.92 (m, 1H), 0.80-0, 68 (m, 2H).

Stage I. 1,2-Diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

The title compound 1,2-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride was obtained in the same way as in Example 26, step C, using (2-acetamido-2- (tert-butylcarbamoyl) - Benzyl 4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) carbamate (diastereoisomer A, 70 mg, 0.13 mmol, 1 equiv. ) and 6N HClac (4 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a single A diastereoisomer (6.7 mg, 17%, white solid). ESI + MS: m / z = 231.1 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.58 (dd, J = 12.1, 5.1 Hz, 1H), 2.44 (dt, J = 13.1, 2.7 Hz, 1H), 2.21-2.06 (m, 2H), 2.01-1.93 (m, 1H), 1.64-1.52 (m, 1H), 1.44-1.35 (m, 3H ), 1.12 (qd, J = 13.3, 4.2 Hz, 1H), 0.85-0.80 (m, 2H).

The second diastereoisomer was obtained in the same way starting from: (2-acetamido-2- (fercbutylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 Benzyl -yl) ethyl) cyclohexyl) carbamate (diastereoisomer B, 35 mg, 0.06 mmol,

1 equiv.) And 6N HClac (3 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a single diastereoisomer (6.5 mg, 33%, white solid). ESI + MS: m / z = 231.2 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.92 (dd, J = 13.3, 4.4 Hz, 1H), 2.24-2.12 (m, 2H), 2.08-1.99 (m, 1H), 1.85-1.75 (m, 1H), 1.75-1.69 (m, 1H), 1.58-1.49 (m, 1H), 1.42 (tt , J = 13.1.6.3 Hz, 2H), 1.31-1.20 (m, 1H), 0.82 (t, J = 8.3 Hz, 2H).

Example 49. 1-Amino-5- (2-boronoethyl) -2- (hydroxymethyl) cyclohexanecarboxylic acid hydrochloride

3) N a B H tO A ch

Stage A. 1-Acetam¡do-N- (fe / 'c-but¡l) -2- (hydrox¡met¡l) -5-v¡n¡lc¡clohexane-1-carboxam¡da

The title compound 1-acetamid-N- (fe / 'c-but¡l) -2- (hydrox¡metal) -5-v¡n¡lc¡clohexane-1-carboxam¡da was obtained in the same way as in Example 26, step A, using rac-2 - ((1S, 2R, 4R) -2-acetamide-2- (tert-butycarbamoil) -4 -v¡n¡lc¡clohex¡l) ethyl acetate (0.3 g, 0.88 mmol, 1 equiv.), 1M DIBAL-H in DCM (2.74 mL, 2.74 mmol, 3 , 1 equ¡v.), Glacial acetic acid (0.25 mL, 4.42 mmol, 5 equ¡v.), 2,2,6,6-tetramethylp¡per¡d Na (0.30 mL, 1.77 mmol, 2 equiv.), Sodium trioxy borohydride (0.75 g, 3.54 mmol, 4 equiv.), DCM dry (30 mL). The residue was purified by silica gel flash chromatography (hexane gradient elution: AcOEt 10: 1 to 1:10) to provide the corresponding product

1-acetamide-N- (fe / 'c-but¡l) -2- (hydroxymetal) -5-v¡n¡lc¡clohexane-1-carboxamide as a mixture of 1: 1 diastereoisomers (0.21g, 80%, white solid). ESI + MS: m / z = 297.2 (M + 1) +, ESI-MS: m / z = 295.0 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 57.70 (s, 1H), 7.41 (s, 1H), 5.78 -5.69 (m, 1H), 4.99 (dt, J = 17 , 3.11.5 Hz, 1H), 4.93 (dt, J = 10.4, 1.4 Hz, 1H), 4.24-4.14 (m, 1H), 3.76-3, 68 (m, 1H), 3.24-3.10 (m, 1H), 2.23-2.16 (m, 1H), 1.97 (s, 3H), 1.94-1.78 ( m, 2H), 1.75-1.65 (m, 1H), 1.34 (s, 9H), 1.28-1.11 (m, 3H).

Step B. 1-Acetamid-N- (fe / 'c-butyl) -2- (hydroxymethyl) -5- (2- (4,4,5,5-tetramethyl) l-1,3,2-d¡oxaborolan-2-¡l) ethylo) cyclohexanecarboxamide

The title compound 1-acetamide-N- (fe / 'c-butyl) -2- (hydroxymethyl) -5- (2- (4,4,5,5-tetramet L-1,3,2-d¡oxaborolan-2-¡l) eth¡l) cyclohexanecarboxamida was obtained in the same way as in Example 26, step B, using 1-acetamid -N- (fe / 'c-but¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) -5-v¡n¡lc¡clohexanecarboxam¡da (0.20g, 0 , 68 mmol, 1 equiv.), Dppe (0.016 g, 0.04 mmol,

0.06 equ¡v.), B¡s (1,5-cyclooctadene) d¡¡r¡d¡o (I) dichloride (0.014g, 0.02mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.13 mL, 0.88 mmol, 1.3 eq). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 10: 1 to 1: 110) to provide the corresponding product 1-acetamine. do-N- (fe / 'c-butyl) -2- (hydroxymethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -d¡oxaborolan-2-¡l) ethyl) cyclohexanecarboxamida as a mixture of diastereomers 1: 1 (0.17g, 59%, white solid). ESI + MS: m / z = 425.4 (M + 1) +, ESI-MS: m / z = 423.2 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 57.67 ( s, 1H), 7.34 (s, 1H), 4.34-4.03 (m, 1H), 3.76-3.58 (m, 1H), 3.17-2.94 (m, 1H), 1.95 (s, 3H), 1.87-1.73 (m, 2H), 1.73-1.65 (m, 1H), 1.53 (s, 9H), 1.51 -1.48 (m, 2H), 1.33 (br s, 5H), 1.28-1.24 (m, 2H), 1.23 (br s, 7H), 1.10-1.05 (m, 1H), 1.00-0.92 (m, 1H), 0.86-0.76 (m, 1H), 0.76-0.68 (m, 1H).

Step C. 1-Amino-5- (2-boronoethyl) -2- (hydroxymethyl) acid hydrochloride

The title compound 1-amino-5- (2-boronoethyl) -2- (hydroxymethyl) acid hydrochloride was obtained in the same way as in Example 26, step C, using the compound 1-acetamido-N- ( tert-butyl) -2- (hydroxymethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide as a mixture of diastereoisomers (0, 10g, 0.23 mmol, 1 equiv.), 6N HClac (3 mL). The residue was purified by preparative HPLC (0.1 -5% MeCN in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the 1-amino-5- (2-boronoethyl) -2 acid hydrochloride product - (hydroxymethyl) cyclohexanecarboxylic as a mixture of diastereoisomers (0.058g, 89%, white solid).

First mixture of diastereoisomers dr = 17: 3 (5.9mg, white solid) ESI + MS: m / z = 228.2 (M-H2O + 1) +, ESI-MS: m / z = 244.0 (M -1)-. 1H NMR (700 MHz, Deuterium Oxide) 84.61, 3.62 [(2dd, J = 9.9, 5.3 Hz, J = 11.3, 4.9 Hz, 1H, two diastereoisomers)], 4.18, 3.55 [(2dd, J = 9.98, 1.46 Hz, 1H, two diastereoisomers)], 2.69-262 (m, 1H), 2.30 (ddd, J = 13.3, 3.4, 1.2 Hz, 1H), 2.09 (ddt, J = 14.8, 6.5, 4.3 Hz, 1H), 1.73-1.56 [(m , 1H, two diastereoisomers)], 1.39 (dd, J = 13.4, 12.3 Hz, 1H), 1.37-1.31 (m, 2H), 1.31-1.26 [( m, 1H, two diastereoisomers)], 1.22-1.07 [(m, 1H, two diastereoisomers)], 0.97-0.85 [(m, 1H, two diastereoisomers)], 0.76-0 , 69 (m, 2H).

Second mixture of diastereoisomers dr = 13: 7 (11.8mg, white solid)) ESI + MS: m / z = 246.2 (M + 1) +, 228.2 (M-H2O + 1) +, ESI- MS: m / z = 244.0 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 84.61, 3.64 [(2dd, J = 10.0, 5.3 Hz, J = 11.4, 4.9 Hz 1H, two diastereoisomers)], 4 , 18, 3.54 [(2dd, J = 10.0, 1.5 Hz, 1H, two diastereoisomers)], 2.69-2.61 (m, 1H), 2.32-2.27 (m , 1H), 2.14-2.06 (m, 1H), 1.84-1.68 (m, 1H), 1.36-1.31 (m, 1H), 1.37-1.31 (m, 2H), 1.30-1.16 [(m, 1H, two diastereoisomers)], 1.15-1.08 (m, 1H), 0.99-0.84 (m, 1H), 0.73 (td, J = 9.2, 6.2 Hz, 2H).

Third mixture of diastereoisomers dr = 3: 2 (6.7mg, white solid) ESI-MS: m / z = 244.0 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 4.61 (dd , J = 9.9, 5.3 Hz, 1H), 4.18 (dd, J = 9.9, 1.4 Hz, 1H), 2.67-2.60 [(m, 1H, two diastereoisomers )], 2.32-2.17 (m, 1H), 2.15-2.05 (m, 1H), 1.90-1.77 (m, 1H), 1.75-1.55 ( m, 1H), 1.43-1.24 (m, 3H), 1.24-1.08 (m, 1H), 0.99-0.84 [(m, 1H, two diastereoisomers)], 0 , 77-0.69 (m, 2H).

Comparative Example 50. 1-Amino-5- (2-boronoethyl) -2-hydroxy-2-methylcyclohexanecarboxylic acid hydrochloride

Step A. 1-Methyl-2-oxocyclohex-3-en-1-yl acetate

A mixture of 6-methyl-2-cyclohexenone (1.58g, 14mmol, 1 equiv., Prepared from 2-cyclohexenone using a method from the literature, J. Nat. Prod., 2004, 67, 1939), benzene (135 mL), acetic acid (15 mL), and manganese (III) acetate dihydrate (5g, 21mmol, 1.5 equiv.) Were heated under reflux for 6h. The reaction mixture was filtered through Celite. The filtrate was diluted with ethyl ether and washed with brine. The organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 30: 1 to 5: 1) to provide the corresponding product (500mg, 21%, colorless oil). 1H NMR (700 MHz, Chloroform-d) 86.88 (dddd, J = 9.6, 5.4, 2.6, 1.2 Hz, 1H), 6.03 (ddd, J = 10.1, 2.7, 1.2 Hz, 1H), 2.91 - 2.82 (m, 1H), 2.54-2.47 (m, 1H), 2.43 (dddt, J = 19.3, 10.9, 5.4, 2.7 Hz, 1H), 2.06 (s, 3H), 1.93 (dddd, J = 12.8, 5.4, 2.7, 1.2 Hz, 1H), 1.44 (s, 3H).

Step B. 1-Methyl-2-oxo-4-vinylcidohexyl acetate

The title compound 1-methyl-2-oxo-4-vinylcyclohexyl acetate was obtained in the same way as in step B from the synthesis of intermediate 1, using 1-methyl-2-oxoddohex-3- acetate. en-1-yl (500 mg, 2.97 mmol, 1 equiv.), 1M vinylmagnesium bromide in THF (7.4mL, 7.44 mmol, 2.5 equiv.), HMPA (2.06 mL, 11 , 9 mmol, 4 equiv.), Copper (I) bromide dimethyl sulfide complex (92mg, 0.44mmol, 0.15 equiv.), Trimethylsilyl chloride (1.87mL, 14.85mmol, 5 equiv.) and THF (20 mL). The residue was purified by silica gel flash chromatography (hexane / AcOEt, 30: 1 to 5: 1) to provide the corresponding product as a single diastereoisomer (310 mg, 53%, colorless oil). 1H NMR (700 MHz, Chloroform-d) 55.76 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.09 - 4.97 (m, 2H), 2.73 (tt, J = 10 .0, 5.0 Hz, 1H), 2.66 (ddd, J = 15.2, 4.7, 2.1 Hz, 1H), 2.42 (ddd, J = 13.3, 11.3 , 4.3 Hz, 1H), 2.27 (dd, J = 15.2, 10.5 Hz, 1H), 2.08 (s, 3H), 2.05-1.96 (m, 1H) , 1.91 (ddd, J = 13.4, 5.5, 3.9 Hz, 1H), 1.58-1.54 (m, 1H), 1.46 (s, 3H).

Step C. 2-Acetamido-2- (tert-butylcarbamoyl) -1-methyl-4-vinylcyclohexyl acetate

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -1-methyl-4-vinylcyclohexyl acetate was obtained in the same way as in step C from the synthesis of intermediate 1, using 1- methyl-2-oxo-4-vinylcyclohexyl (310 mg,

1.58 mmol, 1 equiv.), Ammonium acetate (487 mg, 6.32, mol, 4 equiv.), Tert-butylisocyanide (355 ^ L, 3.16 mmol, 2 equiv.) And 2.2, 2-trifluoroethanol (4 mL) as a solvent. The residue was purified by silica gel flash chromatography (hexane / AcOEt 10: 1 to 1: 2) to provide the corresponding product as a single diastereoisomer (300 mg, 56%, white solid). ESI + MS: m / z = 339.2 (M + 1) +; ESI-MS: m / z = 338.1 (M-1) -. 1H NMR (700 MHz, Chloroform- d) 57.66 (s, 1H), 6.27 (s, 1H), 5.68 ( ddd, J = 17.0, 10.4, 6.3 Hz, 1H), 5.08-4.82 (m, 2H), 3.27 (d, J = 11.2 Hz, 1H), 3 .04-2.95 (m, 1H), 2.53-2.42 (m, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.90 (dt, J = 13.2, 3.7 Hz, 1H), 1.80-1.73 (m, 1H), 1.68 (s, 3H), 1.31 (s, 9H), 1.30-1, 24 (m, 1H), 1.24-1.15 (m, 1H).

Step D. 2-Acetamido-2- (tert-butylcarbamoyl) -1-methyl-4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl acetate ) cyclohexyl

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -1-methyl-4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acetate Ethyl) cyclohexyl was obtained in the same way as in Example 26, step B, using 2-acetamido-2- (tert-butylcarbamoyl) -1-methyl-4-vinylcyclohexyl acetate (200 mg, 0.59 mmol, 1 equiv.), dppe (14 mg, 0.035 mmol, 0.06 equiv.), bis (1,5-cyclooctadiene) diiridium (I) dichloride (12 mg, 0.018 mmol, 0.03 equiv.), 4.4 , 5,5-tetramethyl-1,3,2-dioxaborolane (130 ^ L, 0.89 mmol, 1.5 equiv.) And DCM (10 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 5: 1 to 1: 2) to provide the corresponding product as a single diastereoisomer (220 mg, 80%, white solid). ESI + MS: m / z = 467.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.75 (s, 1H), 6.55 (s, 1H), 3.22

(d, J = 12.0 Hz, 1H), 2.53-2.43 (m, 1H), 2.05 (s, 3H), 2.01 (s, 3H), 2.01-1, 97 (m, 1H), 1.90-1.85 (m, 1H), 1.81-1.74

(m, 1H), 1.63 (s, 3H), 1.42-1.36 (m, 1H), 1.30 (s, 9H), 1.22 (s, 12H), 1.21 - 1.17 (m, 1H), 1.08-0.98 (m, 2H), 0.80-0.72 (m, 2H).

Step E. 1-Amino-5- (2-boronoethyl) -2-hydroxy-2-methylcyclohexanecarboxylic acid hydrochloride

The title compound 1-amino-5- (2-boronoethyl) -2-hydroxy-2-methylcidohexanecarboxylic acid hydrochloride was obtained in the same way as in Example 26, step C, using 2-acetamido-2- acetate. (tert-butylcarbamoyl) -1-methyl-4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexyl (200 mg, 0.43 mmol, 1 equiv.) And 6N HClac (4 mL). The residue was purified by preparative HPLC (0.1-5% MeCN in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the corresponding product as a single diastereoisomer (25 mg, 20%, white solid) and the by-product (1-amino-5- (2-boronoethyl) -2-methylcyclohex-2-enecarboxylic acid hydrochloride, Ex. 51) as a single diastereoisomer (1.7 mg, 2%, white solid).

1-Amino-5- (2-boronoethyl) -2-hydroxy-2-methylcyclohexanecarboxylic acid hydrochloride:

ESI + MS: m / z = 246.2 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 52.41-2.32 (m, 1H), 2.20-2.14 (m, 1H), 1.87-1.80 (m, 1H), 1 , 78-1.67 (m, 2H), 1.43-1.36 (m, 3H), 1.35 (s, 3H), 1.15 (qd, J = 14.0, 4.4 Hz , 1H), 0.87-0.73 (m, 2H). Comparative Example 51. 1-Amino-5- (2-boronoethyl) -2-methylcyclohex-2-enecarboxylic acid hydrochloride

Obtained in step E of Comparative Example 50 (1.7 mg, 2%, white solid). ESI + MS: m / z = 228.2 (M + 1) +; ESI-MS: m / z = 226.0 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 55.98 (d, J = 5.6 Hz, 1H), 2.33-2, 24 (m, 2H), 2.00-1.91 (m, 1H), 1.77-1.74 (m, 1H), 1.73 (s, 3H), 1.51 (t, J = 12.9 Hz, 1H), 1.45-1.37 (m, 2H), 0.87-0.78 (m, 2H). Comparative Example 52. 1-Amino-5- (2-boronoethyl) -2- (4-chlorobenzyl) -2-hydroxycyclohexanecarboxylic acid hydrochloride

Step A. 6- (4-chlorobenzyl) cyclohex-2-enone

To a solution of diisopropylamine (10.9 mL, 0.078 mole, 1.5 equiv.) In THF (45 mL) at 0 ° C was added 2.5M n-BuLi in hexanes (29 mL, 0.072 mole, 1.4 equiv.). After stirring for 30 min, the solution was cooled to -78 ° C and 2-cyclohexenone (5 g, 0.052 mol, 1 equiv.) In THF (45 mL) was added dropwise. The solution was stirred for 30 min followed by the dropwise addition of 4-chlorobenzyl bromide (21 g, 0.104 mol, 2 equiv.). After stirring for 30 min at -78 ° C, HMPA (30 mL) was added. The resulting mixture was stirred at -78 ° C for 3 h. Diethyl ether was added to the reaction mixture at 0 ° C and the organic layer was washed with NH4Clsat. and brine. Dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 40: 1 to 10: 1) to provide the corresponding product (6.6 g, 58%, colorless oil). ESI + MS: m / z = 221.2 (M + 1) +.

1H NMR (700 MHz, Chloroform-d) 57.26 - 7.21 (m, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.93 (dt, J = 8.9 , 3.9 Hz, 1H), 6.02 (dt, J = 10.0, 1.7 Hz, 1H), 3.27 (dd, J = 11.5, 6.8 Hz, 1H), 2 , 55-2.48 (m, 2H), 2.36 (dq, J = 19.2, 4.0 Hz, 1H), 2.29 (dddd, J = 19.3, 10.2, 5, 2, 2.8 Hz, 1H), 1.95 (dq, J = 12.9, 4.2 Hz, 1H), 1.67-1.58 (m, 1H).

Step B. 1- (4-chlorobenzyl) -2-oxo-4-vinylcyclohexyl acetate

The suspension of 6- (4-chlorobenzyl) cyclohex-2-enone (3 g, 0.014 mol, 1 equiv.), Lead (IV) acetate (10.6 g, 0.024 mol, 1.75 equiv.) In toluene (16 mL) was refluxed for 28 h. The solvent was evaporated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 20: 1 to 5: 1) to provide the corresponding product (880 mg, 23%, white solid). 1H NMR (700 MHz, Chloroform-d) 57.29 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.95 -6.90 ( m, 1H), 6.11 (dt, J = 10.1, 1.9 Hz, 1H), 3.04 (d, J = 14.4 Hz, 1H), 2.92 (d, J = 14 , 4 Hz, 1H), 2.76 (dt, J = 12.5, 8.2 Hz, 1H), 2.50-2.46 (m, 2H), 2.07 (s, 3H), 1 , 85-1.80 (m, 1H).

Step C. 1- (4-chlorobenzyl) -2-oxo-4-vinylcyclohexyl acetate

The title compound 1- (4-chlorobenzyl) -2-oxo-4-vinylcyclohexyl acetate was obtained in the same way as in step B from the synthesis of intermediate 1, using 1- (4-chlorobenzyl acetate ) -2-oxo-4-vinylcyclohexyl (860 mg, 3.08 mmol,

1 equiv.), 1M vinylmagnesium bromide in THF (7.7 mL, 7.7 mmol, 2.5 equiv.), HMPA (2.15 mL, 12.3 mmol, 4 equiv.), Bromide complex copper (I) dimethyl sulfide (95 mg, 0.46 mmol, 0.15 equiv.), trimethylsilyl chloride (1.94 mL,

15.4 mmol, 5 equiv.) And THF (22 mL). The residue was purified by silica gel flash chromatography (hexane / AcOEt, 15: 1 to 10: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 85:15, (680 mg, 72%, colorless oil ). 1H NMR (700 MHz, Chloroform-d) 57.30 - 7.24 [(m, 2H, two diastereoisomers)], 7.14-7.11 [(m, 2H, two diastereoisomers)], 5.85 - 5.78 [(m, 1H, two diastereoisomers)], 5.13-4.97 [(m, 2H, two diastereoisomers)], 3.15-3.06 [(m, 1H, two diastereoisomers)], 2.99-2.94 [(m, 1H, two diastereoisomers)], 2.83-2.75 (m, 1H), 2.74-2.54 [(m, 1h, two diastereoisomers)], 2 , 34-2.16 [(m, 2H, two diastereoisomers)], 2.08, 2.04 [(2s, 3H, two diastereoisomers)], 2.01-1.90 (m, 1H), 1, 86 -1.64 [(m, 1h, two diastereoisomers)], 1.61-1.54 (m, 1H).

Step D. 2-Acetamido-2- (tert-butylcarbamoyl) -1- (4-chlorobenzyl) -4-vinylcyclohexyl acetate

The title compound 2-acetamide-2- (tert-butycarbamol) -1- (4-chlorobenzyl) -4-vínílcíclohexílo acetate was obtained from the m Same way as in stage C starting from the synthesis of intermediate 1, using 1- (4-chlorobenzl) -2-oxo-4-v¡n¡lddohex¡lo acetate (670 mg, 2.18 mmol, 1 equ¡v.), ethyl amon¡o (672 mg, 8.76 mmol, 4 equ¡v.), tert- but¡l¡soc¡anuro

(490 ^ L, 4.37 mmol, 2 equiv.) And 2,2,2-trifluoroethanol (2 mL) as a solvent. The residue was purified by silica gel flash chromatography (hexane / AcOEt 10: 1 to 1: 6) to provide the corresponding product as a mixture of separable diastereoisomers. Overall yield: 11%.

First diastereoisomer (A): (85 mg, white foam); ESI + MS: m / z = 471.3 (M + Na) +. 1H NMR (700 MHz, Chloroform- d) 58.40 (s, 1H), 7.31-7.27 (m, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6, 20 (s, 1H), 5.74 (ddd, J = 17.0, 10.4, 6.3 Hz, 1H), 5.12-4.87 (m, 2H), 3.80 (d, J = 13.5 Hz, 1H), 3.52-3.40 (m, 1H), 3.16-3.02 (m, 2H), 2.36-2.25 (m, 1H), 2 , 04 (s, 3H), 2.03 (s, 3H), 1.81-1.75 (m, 1H), 1.71 (dt, J = 13.9, 3.5 Hz, 1H), 1.48-1.33 (m, 2H), 1.31 (s, 9H).

Second diastereoisomer (B): (20 mg, white solid); 1H NMR (700 MHz, Chloroform-d) 57.28 - 7.25 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.97 (s, 1H), 5, 91 (s, 1H), 5.79 (ddd, J = 17.2, 10.5, 5.8 Hz, 1H), 5.09-4.97 (m, 2H), 2.88 (d, J = 14.1 Hz, 1H), 2.82 (d, J = 14.3 Hz, 1H), 2.72 (dt, J = 13.3, 2.6 Hz, 1H), 2.12 - 2.06 (m, 1H), 2.05 (s, 3H), 1.81-1.73 (m, 1H), 1.73-1.66 (m, 1H), 1.63 (dt, J = 14.1.3.2 Hz, 1H), 1.54 (s, 3H), 1.46-1.38 (m, 1H), 1.33 (s, 9H), 1.32-1 , 27 (m, 1H).

Step E. 2-Acetamide-2- (tert-butycarbamoil) -1- (4-chlorobenzyl) -4- (2- (4,4,5,5-tetramethyl) acetate -1,3,2-d¡oxaborolan-2-¡l) et¡l) cyclohex¡lo

The title compound 2-acetamide-2- (tert-butycarbamoyl) -1- (4-chlorobenzyl) -4- (2- (4,4,5,5-tetramethyl) acetate l-1,3,2-d¡oxaborolan-2-¡l) eth¡l) cyclohex¡lo was obtained in the same way as in Example 26, step B, using 2-acetamine acetate. do-2- (tert-but¡lcarbamo¡l) -1- (4-chlorobenz¡l) -4-v¡n¡lc¡clohex¡lo (d¡astereo¡somer A, 85 mg, 0.19 mmol , 1 equ¡v.), Dppe (4.5 mg, 0.011 mmol, 0.06 equ¡v.), B¡s (1,5-cyclooctadene) d¡¡r¡ d¡o (I) (3.8 mg, 0.0057 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (41 ^ L, 0.89 mmol, 1.5 equiv.) And DCM (3 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 10: 1 to 2: 1) to provide the corresponding product as a single A dastereomer (70 mg, 64 %, white foam). eS i + MS: m / z = 599.6 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 58.48 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H) , 6.42 (s, 1H), 3.77 (d, J = 14.8 Hz, 1H), 3.42 (d, J = 14.8 Hz, 1H), 3.02 (d, J = 14.8 Hz, 1H), 2.27 (td, J = 14.3, 2.6 Hz, 1H), 2.14-2.06 (m, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.82-1.76 (m, 1H), 1.67 (dt, J = 13.9, 3.3 Hz, 1H), 1.51-1.43 ( m, 1H), 1.30 (s, 9H), 1.24 (s, 12H), 1.22-1.10 (m, 3H), 0.80 (ddd, J = 9.3, 6, 6, 1.6 Hz, 2H).

The second diastereoisomer was obtained in the same way starting from: 2-acetamid-2- (tert-butycarbamoil) -1- (4-chlorobenzyl) - acetate 4-v¡n¡lc¡clohex¡lo (diastereo¡somer B, 20 mg, 0.045 mmol, 1 equ¡v.), Dppe (1 mg, 0.0027 mmol, 0.06 equ¡v.) , b¡s (1,5-cyclooctadene) d¡¡r¡d¡o (I) chloride (0.9 mg, 0.0014 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 ^ L, 0.067 mmol, 1.5 equiv.) And Dc M (2 mL). The crude product was purified ^{by silica gel column síl¡ce (hexane / AcOEt 8: 1 to 2: 1) to Correspond proporc¡onar product} and ^nte as a d¡astereo¡sómero ún¡co B (25 mg , 100%, white solid). 1H Rm N (700 MHz, Chloroform-d) 58.44 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H ), 6.92 (s, 1H), 2.85 (d, J = 14.0 Hz, 1H), 2.79 (d, J = 14.2 Hz, 1H), 2.66 (d, J = 12.3 Hz, 1H), 2.03 (s, 3H), 1.75-1.64 (m, 2H), 1.58 (s, 3H), 1.58-1.53 (m, 1H), 1.50-1.43 (m, 1H), 1.40-1.33 (m, 2H), 1.31 (s, 9H), 1.24 (s, 12H), 1.24 - 1.20 (m, 1H), 1.10-1.02 (m, 1H), 0.78 (dt, J = 9.6, 6.2 Hz, 2H).

Stage F. 1-amino-5- (2-boronoethyl) -2- (4-chlorobenzl) -2-hydroxy-cyclohexanecarboxylic acid hydrochloride

The title compound 1-amino-5- (2-boronoethyl) -2- (4-chlorobenzl) -2-hydroxy-cyclohexanecarboxylic acid hydrochloride was obtained in the same manner as in Example 26, step C, using 2-acetamide-2- (tert-butycarbamoil) -1- (4-chlorobenzyl) -4- (2 - (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) cyclohexyl (diastereomer A, 70 mg, 0 , 12 mmol, 1 equiv.) And 6N HClac (3mL). The residue was purified by preparative HPLC (5 -50% MeCN in water) to provide (after acidification with 6N HCl and subsequent liofilization) the product ^{corresponds as a single A diastereoisomer (6.1 mg, 13%, white solid) and the by-product acid} hydrochloride (1-amine-5- ( 2-boronoethyl) -2- (4-chlorobenzyl) cyclohex-2-enecarboxylic, Comparative Example 53) as a single diastereomer (6.3 mg, 13% , white solid). ESI + MS: m / z = 356.3 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 57.45 -7.40 (m, 2H), 7.38 - 7.34 (m, 2H), 3.11 (d, J = 13, 4Hz, 1H), 2.77 (d, J = 13.3Hz, 1H), 2.28 (dd, J = 13.8, 2.3 Hz, 1H), 2.11-1.97 (m, 2H), 1.80-1.73 (m, 1H), 1.61-1.55 (m, 1H) , 1.51-1.40 (m, 3H), 1.29-1.19 (m, 1H), 0.84 (td, J = 7.7, 2.9 Hz, 2H).

The second diastereoisomer was obtained in the same way starting from: 2-acetamido-2- (fercbutylcarbamoyl) -1- (4-dorobenzyl) -4- (2- (4,4,5,5-tetramethyl) acetate 1,3,2-dioxaborolan-2-yl) ethyl) cydohexyl (diastereoisomer B, 25 mg, 0.43 mmol, 1 equiv.) And 6N HClac (3mL). The residue was purified by preparative Hp Lc (5-50% MeCN in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the corresponding product as a single B diastereoisomer (25 mg, 70%, white solid). ESI + MS: m / z = 356.4 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 57.43 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 3.11 (d, J = 13.4 Hz, 1H), 2.77 (d, J = 13.3 Hz, 1H), 2.32-2.26 (m, 1H), 2.10-1.98 (m, 2H), 1.80-1.74 (m, 1H), 1.62-1.55 (m, 1H), 1.49 (dt, J = 13.7, 3.3 Hz, 1H), 1.45 ( q, J = 8.0 Hz, 2H), 1.25 (qd, J = 13.8, 3.6 Hz, 1H), 0.85 (td, J = 7.7, 3.1 Hz, 2H ).

Comparative Example 53. 1-Amino-5- (2-boronoethyl) -2- (4-chlorobenzyl) cyclohex-2-enecarboxylic acid hydrochloride

Obtained in step F of Comparative Example 52 (6.3 mg, 13%, white solid). ESI + MS: m / z = 338.2 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 57.44 - 7.37 (m, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.75 (d, J = 4.3 Hz, 1H), 3.40 (d, J = 15.9 Hz, 1H), 3.27 (d, J = 16.0 Hz, 1H), 2.33 (dt, J = 13.1.2 , 6 Hz, 1H), 2.30-2.23 (m, 1H), 2.01-1.88 (m, 1H), 1.82-1.70 (m, 1H), 1.57 ( t, J = 13.0 Hz, 1H), 1.47-1.38 (m, 2H), 0.87-0.75 (m, 2H).

General synthetic route for Comparative Examples 54 and 55

Comparative Example 54. Rac- (3R, 5R) -1-amino-3- (aminomethyl) -5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

Step A. 3 - ((ferc-Butyldimethylsilyl) oxy) -5-vinylcyclohexanone

The title compound 3 - ((tert-but¡ld¡met¡ls¡l¡l) ox¡) -5-v¡n¡lc¡clohexanone was obtained in the same way as in step B from of the synthesis of intermediate 1, using 5 - ((tert-but¡ld¡met¡ls¡l¡l) ox¡) cyclohex-2-enone (1.77 g, 7.8 mmol, 1 equiv., prepared from 1,3,5-cyclohexanotrole using a method from bibliography, J. Org. Chem, 2001, 66, 8277), bromide of 1M magnesium in THF (27.3 mL, 27.3 mmol, 3.5 equiv.), HMPA (5.4 mL, 31.2 mmol, 4 equiv.), copper (I) bromide complex, dimethyl sulfide (242 mg, 1.17 mmol, 0.15 equiv.), trimethyl chloride (4.9 mL, 39.0 mmol, 5 equiv.) And THF (50 mL). The residue was purified by silica gel flash chromatography (hexane / AcOEt, 100: 1 to 10: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 9: 1, (1.5 mg, 76%, light yellow oil). ESI + MS: m / z = 255.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 55.81 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H), 5.10 -5.00 [(m, 2H, two d¡ astereo¡somers)], 4.43-3.88 [(m, 1H, two diastereo¡somers)], 2.98 2.78 [(m, 1H, two diastereo¡somers)], 2 , 64-2.29 [(m, 3H, two diastereoisomers)], 2.17-2.10 [(m, 1H, two diastereoisomers)], 1.98-1.90 (m, 1H), 1.68-1.52 [(m, 1H, two diastereoisomers)], 0.88, 0.82 [(2s, 9H, two diastereoisomers)], 0.07, 0.05 [(2d, J = 7.7 Hz, J = 4.8 Hz, 6H, two diasteriosomers)].

Stage B. 5-V¡n¡lc¡clohex-2-enone

At a solution of 3 - ((tert-but¡ld¡met¡ls¡l¡l) ox¡) -5-v¡n¡lc¡clohexanone (1.5 g, 5.9 mmol, 1 equiv.) In dichloromethane was added p-toluenesulfonic acid monohydrate (0.33 g, 1.7 mmol, 0.3 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was flushed with NaHCO3 (sat) and extracted with dichloromethane three times. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (DCM) to provide the corresponding product (700 mg, 97%, light yellow oil). ESI + MS: m / z = 123.0 (M + 1) +.

1H NMR (700 MHz, Chloroform-d) 56.97 (ddd, J = 10.1, 5.5, 2.8 Hz, 1H), 6.05 (ddt, J = 10.1,2.6, 1.2 Hz, 1H), 5.83 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H), 5.13-4.95 (m, 2H), 2.86-2 , 73 (m, 1H), 2.57 (dd, J = 16.3, 4.1 Hz, 1H), 2.52-2.46 (m, 1H), 2.31 (dd, J = 16 , 3.12.2 Hz, 1H), 2.24 (ddt, J = 18.6, 9.9, 2.7 Hz, 1H).

Stage C. rac- ( 3R, 5R) - 3- (Nitromethyl) -5-v¡n¡lc¡clohexanone

At a dilution of 5-v¡n¡lc¡clohex-2-enone (266 mg, 2.18 mmol, 1 equ¡v.) In acetonitric (7 mL), was added eron nitromethane (0.6 mL, 10.9 mmol, 5 equiv.) and 1,8-diazabicclo [5.4.0] undec-7-ene (0.49 mL, 3 , 27 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo. The residue was purified by silica gel flash chromatography (hexane / DCM, 5: 1 to 1: 9) to provide the ^{corresponding product as a single diastereoisomer (85 mg , 21%, colorless oil). 1H NMR (700 MHz, Chloroform-d)} 5.77 (ddd, J = 17.3, 10.6, 5.4 Hz, 1H), 5.16 -5.01 (m, 2H), 4, 47-4.27 (m, 2H), 2.97-2.82 (m, 2H), 2.58-2.43 (m, 3H), 2.18 (dd, J = 14.4.9 , 9 Hz, 1H), 1.92 (dt, J = 13.3, 4.6 Hz, 1H), 1.81 (ddd, J = 13.8, 9.5, 4.4 Hz, 1H) .

Step D. rac- (3R, 5R) -1-Acetamide-N- (tert-butyl) -3- (nitromethyl) -5-v¡n¡lc¡clohexanecarboxam¡da

The title compound rac- (3R, 5R) -1-acetamide-N- (tert-butyl) -3- (nitromethyl) -5-v¡n¡lcyclohexanecarboxamide is obtained in the same way as in stage C from the synthesis of intermediate 1, using (3R, 5R) -3- (n¡tromet¡l) -5-v¡n Cyclohexanone (70 mg, 0.38 mmol, 1 equiv), ammonium acetate (120 mg, 1.52 mmol, 4 equiv), tert- butylsocyanide (86 ^ L, 0.76 mmol, 2 equiv.) And 2,2,2-trifluoroethanol (4 mL) as a solvent. The res¡duo was purified ^{by flash silica gel síl¡ce (DCM / methanol 100: 1 to 70: 1) to Correspond proporc¡onar product} and ^nte as a m ezc la de d ia s te re o isó me ro s sep a ra b le s. I know a single day s re o isó me ro. In addition, the m ezc la de d ia s te re o isó me ro s was also isolated (dr = 85: 15). R e nd im ie n to g loba l: 80%.

Diastereoisomer mixture (85:15): (20 mg, white solid); ESI + MS: m / z = 326.2 (M + 1) +. Major diastereoisomer

1H NMR (700 MHz, Chloroform-d) 56.83 (s, 1H), 5.98 (ddd, J = 17.6, 10.8, 4.8 Hz, 1H), 5.71 (s, 1H ), 5.25 -5.14 (m, 2H), 4.35 (dd, J = 12.6, 5.5 Hz, 1H), 4.25 (dd, J = 12.6, 9.0 Hz, 1H), 2.79-2.68 (m, 1H), 2.64-2.51 (m, 1H), 2.30 (d, J = 14.7 Hz, 1H), 2.10 (d, J = 4.7 Hz, 2H), 1.97 (s, 3H), 1.97-1.93 (m, 1H), 1.81-1.73 (m, 1H), 1, 43-1.36 (m, 1H), 1.31 (s, 9H).

Single diastereoisomer (80 mg, white solid); ESI + MS: m / z = 326.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.02 (s, 1H), 5.87 (s, 1H), 5.76 (ddd, J = 17.1, 10.4, 6.4 Hz, 1H ), 5.11-4.98 (m, 2H), 4.56 (dd, J = 11.5, 8.2 Hz, 1H), 4.49 (dd, J = 11.5, 7.9 Hz, 1H), 2.93-2.85 (m, 1H), 2.43-2.26 (m, 2H), 2.15 (dd, J = 15.2, 5.7 Hz, 1H) , 2.06 (s, 3H), 2.05-2.04 (m, 1H), 1.92-1.83 (m, 1H), 1.67-1.61 (m, 1H), 1 , 62-1.55 (m, 1H), 1.31 (s, 9H).

Step E. rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide

The title compound rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -5- (2- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide was obtained in the same way as in Example 26, step B, using rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3- ( nitromethyl) -5-vinylcyclohexanecarboxamide (mixture of diastereoisomers 85:15, 20 mg,

0.06 mmol, 1 equiv.), Dppe (1.4 mg, 0.0036 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (1.2 mg, 0 0.0018 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13 ^ L, 0.09 mmol, 1.5 equiv.) And Dc M (1 mL ). The crude product was purified by silica gel column chromatography (hexane / AcOEt 8: 1 to 1: 2) to provide the corresponding product as a mixture of diastereoisomers, dr. = 85:15 (27 mg, 97%, colorless oil). ESI + MS: m / z = 454.3 (M + 1) +; ESI-MS: m / z = 452.3 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 57.19, 7.00 [(2s, 1H, two diastereoisomers)], 6.00, 5.85 [(2s, 1H, two diastereoisomers)], 4.52 - 4.24 [(m, 2H, two diastereoisomers)], 2.83-2.50 [(m, 1H, two diastereoisomers)], 2.32-2.24 (m, 1H), 2.16-2 , 10 (m, 1H), 2.04, 2.03 [(2s, 3H, two diastereoisomers)], 1.93 (dd, J = 13.9, 9.4 Hz, 1H), 1.82 - 1.74 (m, 2H), 1.66-1.58 (m, 1H), 1.53-1.49 (m, 1H), 1.48-1.41 (m, 2H), 1, 32, 1.31 [(2s, 9H, two diastereoisomers)], 1.25, 1.24 [(2s, 12H, two diastereoisomers)], 0.93-0.84 (m, 1H), 0.83 - 0.73 (m, 1H).

The second diastereoisomer was obtained in the same way starting from: rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -5-vinylcyclohexanecarboxamide (single diastereoisomer, 80 mg, 0, 24 mmol, 1 equiv.), Dppe (5.7 mg,

0.014 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (4.8 mg, 0.007 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (55 ^ L, 0.37 mmol, 1.5 equiv.) And DCM (8 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 8: 1 to 1: 4) to provide the corresponding product as a single diastereoisomer (100 mg, 90%, white solid). ESI + MS: m / z = 454.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.02 (s, 1H), 5.86 (s, 1H), 4.96-4.24 (m, 2H), 2.87-2.79 (m , 1H), 2.38-2.30 (m, 1H), 2.19-2.11 (m, 2H), 2.06 (s, 3H), 1.67-1.58 (m, 2H ), 1.47-1.35 (m, 3H), 1.33 (s, 9H), 1.29-1.26 (m, 1H), 1.26 (s, 12H), 0.80 ( t, J = 8.0 Hz, 2H).

Step F. rac - (((1 R, 5R) -3-acetamido-3- (tert-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Te / c -butyl 2-yl) ethyl) cyclohexyl) methyl) carbamate

A solution of rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (mixture of diastereoisomers 85:15, 20 mg, 0.044 mmol, 1 equiv.) in methanol (1 mL) was cooled to -20 ° C and di-tert-dicarbonate was added. butyl (20 mg, 0.088 mmol, 2 equiv.), chloride hexahydrate nickel (II) (10 mg, 0.044 mimols, 1 equiv.) and sodium borohydride (17 mg, 0.44 mimols, 10 equiv.) in parts. The mixture was allowed to warm to room temperature and stirred for 3 h. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with H ² O, ^{sat NH 4} Cl, and brine. The organic layer was dried over MgSO ⁴ , filtered and concentrated in vacuo to provide the corresponding product as a mixture of diastereoisomers, dr. = 85:15, (20 mg, 87%, white solid). ESI + MS: m / z = 524.0 (M + 1) ⁺ . ¹ H NMR (700 MHz, Chloroform-d) 67.12, 7.07 [(2s, 1H, two diastereomers)], 5.82 (s, 1H), 4.91 to 4.72 [(m, 1H , two diastereoisomers)], 3.12-3.04 (m, 1H), 3.10-2.79 [(m, 1H, two diastereoisomers)], 2.24-2.13 (m, 1H), 2.05-1.99 (m, 1H), 1.98, 1.96 [(2s, 3H, two diastereoisomers)], 1.91-1.78 (m, 3H), 1.80-1, 74 (m, 1H), 1.73-1.63 (m, 1H), 1.60-1.55 (m, 1H), 1.46, 1.44 [(2s, 9H, two diastereoisomers)] , 1.36-1.33 (m, 1H), 1.31, 1.30 [(2s, 9H, two diastereoisomers)], 1.28-1.24 (m, 1H), 1.24.1 , 23 [(2s, 12H, two diastereoisomers)], 0.90-0.80 (m, 1H), 0.80-0.74 (m, 1H).

The second diastereoisomer was obtained in the same way starting from: rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3- (nitromethyl) -5- (2- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (single diastereoisomer, 100 mg, 0.22 mmol, 1 equiv.), Di-tert-butyl dicarbonate (95 mg, 0.44 mmol, 2 equiv.), nickel (II) chloride hexahydrate

(52 mg, 0.22 mmol, 1 equiv.) And sodium borohydride (83 mg, 2.2 mmol, 10 equiv.) And methanol (5 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 5: 1 to 1: 9) to provide the corresponding product as a single diastereoisomer (78 mg, 68%, white solid). ESI + m S: m / z = 524.0 (M + 1) ⁺ . ¹ H NMR (700 MHz, Chloroform-d) 68.03 (s, 1H), 7.07 (s, 1H), 4.85 to 4.67 (m, 1H), 3.76 to 3.51 ( m, 1H), 2.97-2.66 (m, 2H), 2.06

(s, 3H), 1.97-1.85 (m, 3H), 1.77-1.70 (m, 1H), 1.46 (s, 9H), 1.42-1.31 (m , 2H), 1.30 (s, 9H), 1.23 (s, 12H), 1.21-1.13 (m, 2H), 0.78-0.71 (m, 2H).

Step G. Rac- (3R, 5R) -1-amino-3- (aminomethyl) -5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

The title compound rac- (3R, 5R) -1-amino-3- (aminomethyl) -5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26, step C, using ( ((1R, 5R) -3-acetamido-3- (tert-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl ) racemic tert-butyl) methyl) carbamate (mixture of 85:15 diastereoisomers, 20 mg, 0.038 mmol, 1 equiv.) and ^{6N aq} HCl (3 mL). The residue was purified by flash chromatography on a DOWEX ^® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a mixture of diastereoisomers, dr = 85:15 (4.7 mg, 31%, white solid). ESI + MS: m / z = 245.1 (M + 1) ⁺ . ¹ H NMR (700 MHz, Deuterium Oxide) 6 3.12 - 2.97 [(m, 2H, two diastereoisomers)], 2.47-2.29 [(m, 3H, two diastereoisomers)], 1, 93, 1.86 [(2dd, J = 14.4, 5.3 Hz, J = 14.0, 4.9 Hz, 1H, two diastereoisomers)], 1.84-1.73 (m, 1H) , 1.72 (dt, J = 14.1, 4.4 Hz, 1H), 1.53-1.36 (m, 4H), 0.87-0.80 [(m, 2H, two diastereoisomers) ].

The second diastereoisomer was obtained in the same way starting from: (((1R, 5R) -3-acetamido-3- (tert-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1, Racemic tert-butyl 3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) methyl) carbamate (single diastereoisomer, 20 mg, 0.038 mmol, 1 equiv.) And ^{6N aq} HCl (3 mL). The residue was purified by flash chromatography on a DOWEX ^® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a single diastereoisomer (4.9 mg, 41%, white solid). ESI + MS: m / z = 245.1 (M + 1) ⁺ . ¹ H NMR (700 MHz, Deuterium Oxide) 63.08-293 (m, 2H), 2.52-2.27 (m, 3H), 1.97-1.90 (m, 1H), 1.87 (dd, J = 14.0, 5.0 Hz, 1H), 1.76 (d, J = 13.4 Hz, 1H), 1.51 - 1.30 (m, 4H), 0 , 81 (td, J = 8.1, 4.5 Hz, 2H).

Comparative Example 55. Rac- (3R, 5R) -1-amino-3- (2-boronoethyl) -5 - ((dimethylamino) methyl) acidhexanecarboxylic acid dihydrochloride

Step H. rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3 - ((dimethylamino) methyl) -5- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) cidohexanecarboxamide

To a solution of (((1R, 5R) -3-acetamido-3- (tert-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Racemic tert-butyl yl) ethyl) cyclohexyl) methyl) carbamate (46 mg, 0.088 mmol, 1 equiv.) (second diastereoisomer) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1.5 h. The solvents were evaporated in vacuo. The residue was dissolved in 1,2-dichloroethane (i mL) and formaldehydeac (25 L, 0.34 mmol, 4 equiv.) Was added and stirred at room temperature for 1h. Then, sodium triacetoxyborohydride (72 mg, 0.34 mmol, 4 equiv.) Was added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with 5% NaHCO3. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the corresponding product as a single diastereoisomer (30 mg, 76%, white solid). ESI + MS: m / z = 452.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.88 (s, 1H), 7.56 (s, 1H), 3.01-2.76 (m, 1H), 2.52 (t, J = 13 , 3Hz, 1H), 2.22 (s, 6H), 2.18-2.14 (m, 1H), 1.99-1.97 (m, 2H), 1.96 (s, 3H) , 1.84-1.78 (m, 1H), 1.43-1.37 (m, 2H), 1.31 (s, 9H), 1.29-1.24 (m, 2H), 1 , 23 (s, 12H), 1.16-1.10 (m, 2H), 0.76 (dt, J = 9.5, 6.3 Hz, 2H).

Step I. Rac- (3R, 5R) -1-amino-3- (2-boronoethyl) -5 - ((dimethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride

The title compound rac- (3R, 5R) -1-amino-3- (2-boronoethyl) -5 - ((dimethylamino) methyl) cyclohexanecarboxylic acid hydrochloride was obtained in the same manner as in Example 26, step C , using rac- (3R, 5R) -1-acetamido-N- (tert-butyl) -3 - ((dimethylamino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) ethyl) cyclohexanecarboxamide (30 mg, 0.07 mmol, 1 equiv.) And 6N HClac (3 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6n and subsequent lyophilization) the corresponding product as a single diastereoisomer (1.2 mg, 5%, white solid). ESI + MS: m / z = 273.2 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.15 (d, J = 7.5 Hz, 2H), 2.96 (d, J = 12.9 Hz, 6H), 2.65 - 2.51 ( m, 1H), 2.38-2.31 (m, 2H), 1.97-1.87 (m, 1H), 1.84 (dd, J = 14.1.5.0 Hz, 1H) , 1.74-1.68 (m, 1H), 1.53-1.30 (m, 4H), 0.88-0.70 (m, 2H).

Comparative Example 56. 1,3-Diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride

Stage A. 3-Azido-5-vinylcidohexanone

Acetic acid was added to a solution of trimethylcellulose azide (3.87 mL, 29.5 mmol, 5 equiv.) In dichloromethane (25 mL).

(1.68 mL, 29.5 mmol, 5 equiv.) And stirred at room temperature for 20 min. Then, 5-vinylcidohex-2-enone (0.72 g, 5.9 mmol, 1 equiv.) In dichloromethane (5 mL) was added followed by the addition of 1,8-diazabicide [5.4.0] undec-7- ene (176 ^ L, 1.18 mmol, 0.2 equiv.). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with dichloromethane and washed with H2O, 5% NaHCO3. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to provide the corresponding product as a mixture of dlastereolsomers, dr = 85:15, (0.9 g, 93%, orange oil). 1H NMR (700 MHz, Chloroform-d) 5.85 -5.75 [(m, 1H, two dlastereolsomers)], 5.13 -5.03 (m, 2H), 4.22-3.63 [ (m, 1H, two dlastereolsomers)], 2.89-2.72 [(m, 1H, two dlastereolsomers)], 2.59-2.54 (m, 1H), 2.53-2.38 [( m, 2H, two dlastereolsomers)], 2.36-2.24 [(m, 1H, two dlastereolsomers)], 2.16 (t, J = 13.5 Hz, 1H), 2.10-2.02 (m, 1H), 1.85-1.55 [(m, 1H, two dlastereolsomers)].

Step B. tere-butyl (3-Oxo-5-vinylcyclohexyl) carbamate

To a solution of 3-azido-5-vinylcyclohexanone (0.9 g, 5.45 mmol, 1 equiv.) In tetrahydrofuran (10 mL) was added triphenylphosphine (2.85 g, 10.9 mmol, 2 equiv.) and H2O (0.49 mL, 27.2 mmol, 5 equiv.). The reaction mixture was stirred at room temperature for 3 h. Then, sodium bicarbonate (0.91 g, 10.9 mmol, 2 equiv.), Di-tere-butyl dicarbonate (1.42 g, 6.54 mmol, 1.2 equiv.) Were added to the mixture. and H2O (10 mL). The resulting mixture was stirred at room temperature for 2 days. The mixture was diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 50: 1 to 3: 1) to provide the corresponding product as a mixture of dlastereolsomers, dr. = 85:15,

(200mg, 15%, white solid). ESI + MS: m / z = 184.0 (M-ffiu) +. 1H NMR (700 MHz, Chloroform-d) 55.82 -5.75 [(m, 1H, two dlastereolsomers)], 5.17 -5.00 (m, 2H), 4.42, 4.21 [( 2br s, 1H, two dlastereolsomers)], 2.75-2.71 (m, 1H), 2.61 (dd, J = 14.3, 5.1 Hz, 1H), 2.49-2.38 (m, 2H), 2.37-2.26 [(m, 2H, two diastereisomers)], 2.20-2.02 [(m, 1H, two dlastereolsomers)], 1.85-1.82 ( m, 1H), 1.45, 1.43 [(2s, 9H, two dlastereolsomers)].

Step C. (3-Acetamide-3- (tere-butylcarbamoil) -5-v¡n¡lcyclohexl) tere-butyl carbamate

The title compound (3-acetamide-3- (tere-butylcarbamoil) -5-v¡n¡lcyclohexyl) tere-butyl carbamate was obtained in the same way as in step C a starting from the synthesis of intermediate 1, using tere-butyl (3-oxo-5-v¡n¡lddohexl) carbamate (200 mg, 0.84 mmol, 1 equiv.), ammonium (258 mg, 3.36 mmol, 4 equiv.), tere-butylisocyanide

(187 ^ L, 1.67 mmol, 2 equiv.) And 2,2,2-trifluoroethanol (8 mL) as a solvent. The residue was purified by silica gel flash chromatography (hexane / AcOEt 12: 1 to 2: 1) to provide the corresponding product as a mixture of diastereoisomers. Overall yield: 78%. The diastereoisomers were partially separated as the following diastereoisomeric ratios:

Diastereoisomer mixture (dr = 9: 1): (140 mg, white solid); ESI + MS: m / z = 382.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 56.96, 6.76 [(2s, 1H, two diastereoisomers)], 5.93, 5.86 [(2s, 1H, two diastereoisomers)], 5.74 ( ddd, J = 17.0, 10.4, 6.2 Hz, 1H), 5.07-5.00 [(m, 2H, two diastereoisomers)], 4.61.4.45 [(2d, J = 6.0 Hz, J = 9.4 Hz, 1H, two diastereoisomers)], 4.01-3.63 [(m, 1H, two diastereoisomers)], 2.62, 2.55 [(2d, J = 12.2 Hz, J = 13.2 Hz, 1H, two diastereoisomers)], 2.40 (d, J = 14.1 Hz, 1H), 2.28-2.17 [(m, 1H, two diastereoisomers)], 2.05, 2.03 [(2s, 3H, two diastereoisomers)], 1.82 (dd, J = 15.0, 4.1 Hz, 2H), 1.69-1.49 [ (m, 1H, two diastereoisomers)], 1.46, 1.44 [(2s, 9H, two diastereoisomers)], 1.31 (s, 9H).

Mixture of diastereoisomers (1: 1), (110 mg, white solid); ESI + MS: m / z = 382.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.14, 5.65 [(2s, 1H, two diastereoisomers)], 5.86 -5.69 [(m, 1H, two diastereoisomers)], 5.47 ( s, 2H), 5.17-4.95 [(m, 2H, two diastereoisomers)], 3.97-3.74 [(m, 1H, two diastereoisomers)], 2.95-2.63 [( m, 1H, two diastereoisomers)], 2.36-2.24 [(m, 2H, two diastereoisomers)], 2.04, 1.96 [(2s, 3H, two diastereoisomers)], 2.03 -1 , 85 (m, 1H, two diastereoisomers)], 1.74-1.65 [(m, 2H, two diastereoisomers)], 1.43 (s, 9H), 1.35, 1.33 [(s, 9H, two diastereoisomers)], 1.14-0.96 [(m, 1H, two diastereoisomers)].

Step D. (3-Acetamido-3- (tere-butylcarbamo¡l) -5- (2- (4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l tere-butyl) ethyl) cyclohexyl) carbamate

The title compound (3-acetamido-3- (tere-butylcarbamoil) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-¡ l) ethyl) cyclohexyl) tere-butyl carbamate was obtained in the same manner as in Example 26, step B, using

Tere-butyl (3-acetamide-3- (tere-butycarbamoil) -5-v¡n¡lcyclohexl) carbamate (dr = 9: 1, 140 mg, 0.37 mmol, 1 equiv.), dppe (8.8 mg, 0.022 mmol, 0.06 equiv.), b¡s (1,5-cyclooctadene) dichloride (I) (7, 4 mg, 0.011 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (80 µL, 0.55 mmol, 1.5 equiv.) And DCM (12 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 5: 1 to 1: 1) to provide the corresponding product as a mixture of 9: 1 diastereoisomers (100 mg, 53%, white solid). ESI + MS: m / z = 510.4 (M + 1) +; ESI-MS: m / z = 508.4 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 56.81 (s, 1H), 5.87 (s, 1H), 4.62 ( s, 1H), 4.03-3.88 (m, 1H), 2.55

(d, J = 15.1 Hz, 1H), 2.35 (d, J = 13.7 Hz, 1H), 2.00 (s, 3H), 1.86-1.75 (m, 2H) , 1.56-1.50 (m, 1H), 1.46 (s, 9H), 1.46-1.40 (m, 3H), 1.38-1.32 (m, 1H), 1 , 30 (s, 9H), 1.25 (s, 12H), 0.81 (t, J = 7.6 Hz, 2H).

The second mixture of diastereoisomers was obtained in the same way starting from: (3-acetamido-3- (terebut¡lcarbamo¡l) -5-vinyllc¡clohex¡l) tere-butyl carbamate (dr = 1 : 1,100 mg, 0.26 mmol, 1 equiv.), Dppe (6.2 mg, 0.015 mmol, 0.06 equiv.), Bis (1,5-cyclooctadene) dichloride d Iridium (I) (5.2 mg, 0.0078 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57 ^ L, 0 , 39 mmol, 1.5 equiv.) And DCM (8 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 4: 1 to 1: 1) to provide the corresponding product as a mixture of diastereoisomers, dr. = 1: 1, (116 mg, 87%, white solid). ESI + MS: m / z = 510.4 (M + 1) +; ESI-MS: m / z = 508.4 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 56.02, 5.51 [(2s, 1H, two diastereoisomers)], 5.44, 5.42 [(2s, 1H, two diastereoisomers)], 3.95, 3.69 [(2s, 1H, two diastereoisomers)], 2.62-2.47 [(m, 2H, two diastereoisomers)], 2.02-1.78 [(m, 1H, two diastereoisomers)], 1.97, 1.93 [(2s, 3H, two diastereoisomers)], 1.70-1.60 [(m, 1H, two diastereoisomers)], 1.43, 1.42 [(2s, 9H, two diastereoisomers)], 1.42-1.35 (m, 2H), 1.34, 1.33 [(2s, 9H, two diastereoisomers)], 1.33-1.28 (m, 2H), 1.28-1.23 (m, 1H), 1.24, 1.23 [(2s, 12H, two diastereoisomers)], 1.22-1.15 (m, 1H), 0.83-0.74 (m, 2H).

Step E. 1,3-Diamino-5- (2-boronoethyl) acid hexanecarboxylic acid dihydrochloride

The title compound 1,3-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride was obtained in the same way as in Example 26, step C, using (3-acetamido-3- (tert-butylcarbamoyl) - Tert-Butyl 5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) carbamate (dr = 9: 1, 20 mg, 0.04 mmol, 1 equiv.) and 6N HClac (2 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a single diastereoisomer (3.1 mg, 26%, white solid). ESI + MS: m / z = 231.0 (M + 1) +; ESI-MS: m / z = 229.1 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 84.01 -3.91 (m, 1H), 2.65-2.60 (m, 1H), 2.34 (dd, J = 13.9, 4, 0 Hz, 1H), 2.08-2.00 (m, 2H), 1.82 (dd, J = 14.0, 5.1 Hz, 1H), 1.74-1.63 (m, 2H), 1.48 (dt, J = 16.1, 7.8 Hz, 2H), 0.85-0.69 (m, 2H).

The second mixture of diastereoisomers was obtained in the same way starting from: (3-acetamido-3- (fercbutylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan Tert-Butyl -2-yl) ethyl) cyclohexyl) carbamate (dr = 1: 1, 20 mg,

0.04 mmol, 1 equiv.) And 6N HClac (2 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a mixture of diastereoisomers, dr = 3: 2, (1.6 mg, 13%, white solid). ESI + MS: m / z = 231.0 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 8 3.93-3.89 (m, 1H), 2.64-2.40 [(m, 1H, two diastereoisomers)], 2.36-2.24 [ (m, 1H, two diastereoisomers)], 2.22-2.16 [(m, 1H, two diastereoisomers)], 2.11-1.99 [(m, 1H, two diastereoisomers)], 1.86 - 1.74 (m, 1H), 1.71-1.41 [(m, 3H, two diastereoisomers)], 1.39-1.06 [(m, 1H, two diastereoisomers)], 0.84 (q, J = 6.9 Hz, 2H).

Comparative Example 57. Rac- (3R, 5S) -3-amino-5- (2-boronoethyl) piperidine-3-carboxylic acid dihydrochloride

Step A. tert-Butyl 3-Oxo-5-vinylpiperidine-1-carboxylate

A solution of vinylmagnesium bromide (1M in THF) (14.7 mL, 14.7 mmol) and HMPA (2.92 mL, 16.8 mmol) were added separately dropwise to a suspension of CuBr x Me2S (129 mg, 0.63 mmol) in dry THF (20 mL) at

-78 ° C under argon for 10 min. After stirring at -78 ° C for 15 min, a solution of tert-butyl 5-oxo-5,6-dihydropyridine-1 (2H) -carboxylate (obtained according to the procedure described in WO 2012 / 025155) (0.83 g, 4.2 mmol) and TMSCl (2.67 mL, 21 mmol) in dry THF (10 mL) for 30 min. The reaction mixture was stirred at -78 ° C for 2 h. The mixture was then slowly warmed to room temperature and stirred at room temperature overnight. The mixture was then quenched with saturated aqueous NH4CI (70 mL) and washed with AcOEt

(3 x 100 mL). The crude product (1.95 g) containing HMPA was used in the next step without further purification.

1H NMR (700 MHz, Chloroform-d) 55.78 (ddd, J = 17.0, 10.5, 6.2 Hz, 1H), 5.20 -5.08 (m, 2H), 4.10 (d, J = 18.2 Hz, 1H), 4.02-3.77 (m, 2H), 3.31-3.12 (m, 1H), 2.75 (td, J = 9.4 , 4.5 Hz, 1H), 2.62 (dd, J = 16.5, 4.9 Hz, 1H), 2.38 (dd, J = 16.4, 10.0 Hz, 1H), 1 , 47 (s, 9H).

Step B. Racemic tere-butylcarbamoyl (3R, 5R) - and (3R, 5S) -3-Acetamido-3- (tere-butylcarbamoyl) -5-vinylpiperidine-1-carboxylate

Title compounds were prepared from tere-butyl 3-oxo-5-vinylpiperidine-1-carboxylate (1.9 g, crude) using the procedure described for the preparation of intermediate 1, step C using ammonium acetate ( 2.6 g, 33.7 mmol), t-butyl isocyanide (1.91 mL, 16.87 mmol), and trifluoroethanol (30 mL). Purified by flash column chromatography on silica gel using hexane / AcOEt (20: 1 to 1: 1) as eluents. Overall yield (after two steps): 1.08 g (70%).

tere-butyl rae- (3R, 5R) -3-acetamido-3- (tere-butylcarbamoyl) -5-vinylpiperidine-1-carboxylate; 0.85 g, white solid; ESI + MS: m / z = 368.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.03 (bs, 1H), 5.98 (s, 1H), 5.75 (ddd, J = 17.0, 10.6, 6.0 Hz, 1H ), 5.16 (dt, J = 17.5, 1.4 Hz, 1H), 5.10 (dt, J = 10.6, 1.3 Hz, 1H), 4.40 (d, J = 14.2 Hz, 1H), 3.80 (dd, J = 13.46, 3.39 Hz 1H), 3.50 (d, J = 14.2 Hz, 1H), 3.04 (dd, J = 13.1, 8.7 Hz, 1H), 2.38 (s, 1H), 2.29 (d, J = 12.9 Hz, 1H), 1.95 (s, 3H), 1.50 (s, 9H), 1.35 (s, 9H).

tere-butyl rae- (3R, 5S) -3-acetamido-3- (tere-butylcarbamoyl) -5-vinylpiperidine-1-carboxylate; 0.23 g; white solid; ESI + MS: m / z = 368.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.25 (s, 1H), 6.66 (bs, 1H), 5.67 (ddd, J = 17.2, 10.6,

6.5 Hz, 1H), 5.15-5.04 (m, 2H), 4.30-3.98 (m, 2H), 3.11 (m, 1H), 2.99 (m, 1H ), 2.59 (m, 1H), 2.21 (m, 1H), 2.02 (s, 3H), 1.66 (m, 1H), 1.51 (s, 9H), 1.34 (s, 9H).

Step C. rac- (3R, 5S) -3-Acetamido-3- (tere-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl tere -butyl) ethyl) piperidine-1-carboxylate

Title compounds were prepared from tere-butyl rae- (3R, 5R) -3-acetamido-3- (tere-butylcarbamoyl) -5-vinylpipetidine-1-carboxylate (0.2 g, 0.54 mmol ) using the procedure described in Example 26, step B. The crude product was purified by silica gel flash chromatography (30: 1 to 2: 1 hexane / ethyl acetate). Obtained: 90 mg (white solid) as a mixture of the desired product and the product without pinacol. ESI + MS: m / z = 496.4 (M + 1) +.

Step D. Rae- (3R, 5S) -3-amino-5- (2-boronoethyl) piperidine-3-carboxylic acid dihydrochloride

Title compounds were prepared from (3R, 5S) -3-acetamido-3- (tere-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan Tere-butyl -2-yl) ethyl) piperidine-1-carboxylate (70 mg, 0.14 mmol, mixture from step C) using the procedure described in Example 26, step C. The crude product was purified on Dowex ® 8WX50 and then (after acidification with 6M HClac) by preparative HPLC (0.1-1% MeCN in H2O). Obtained: 7 mg (17%) as a white solid. ESI + MS: m / z = 217.1 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.70 (d, J = 12.4 Hz, 1H), 3.45 (d, J = 8.8 Hz, 1H), 3.03 (d, J = 12.4 Hz, 1H), 2.62 (t, J = 12.5 Hz, 1H), 2.29 (d, J = 13.0 Hz, 1H), 2.00 -1.90 (m, 1H), 1.47 (t, J = 12.8 Hz, 1H), 1.43-1.31 (m, 2H), 0.79-0.65 (m, 2H).

Comparative Example 58. rae- (3R, 5R) -3-amino-5- (2-boronoethyl) piperidine-3-carboxylic acid

Step A. (3R, 5R) -3-Acetamido-3- (tere-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl ) racemic tere-butyl piperidine-1-carboxylate

The title compounds were prepared from racemic tere-butyl (3R, 5S) -3-acetamido-3- (tere-butylcarbamoyl) -5-vinylpiperidine-1-carboxylate (see Comparative Example 57, step B, 130 mg, 0.35 mmol) using the procedure described for the preparation of Example 26, step B. The crude product was purified by flash chromatography on silica gel (DCM / acetone 50: 1 to 2: 1). Obtained: 120 mg (70%) as a white solid. ESI + MS: m / z = 496.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.36 (bs, 1H), 6.65 (bs, 1H) 4.31-3.98 (m, 2H), 3.19-2.87 (m, 2H), 2.44-2.30 (m, 1H), 1.98 (s, 3H), 1.50 (s, 9H), 1.42-1.38 (m, 2H), 1.33 (s, 9H), 1.27-1.26 (m, 2H), 1.26 (d, J = 1.2Hz, 12H), 0.82-0.76 (m, 2H).

Step B. Rae- (3R, 5R) -3-amino-5- (2-boronoethyl) piperidine-3-carboxylic acid

Title compounds were prepared from (3R, 5R) -3-acetamido-3- (tere-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan Racemic tere-butyl -2-yl) ethyl) piperidine-1-carboxylate (100 mg, 0.2 mmol) using the procedure described for the preparation of Example 26. The crude product was purified by preparative HPLC (MeCN 0, 1-1% in H2O) and by Dowex® 8WX50. Obtained: 34 mg (78%) as a white solid. ESI + MS: m / z = 217.1 (M + 1) +. ESI-MS: m / z = 215.1 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 53.29 (d, J = 10.4 Hz, 1H), 3.15-3, 05 (m, 2H), 2.50 (t, J = 12.2 Hz, 1H), 1.90-1.81 (m, 2H), 1.54-1.46 (m, 1H), 1 , 39-1.23 (m, 2H), 0.78-0.66 (m, 2H).

Comparative Example 59. rae- (3R, 5S) -3-amino-5- (2-boronoethyl) -1-methylpiperidine-3-carboxylic acid

Step A. Rae- (3R, 5R) -3-acetamido-W- (tere-butyl) -5-vinylpiperidine-3-carboxamide trifluoroacetate

x CF3C 02H

To the solution of tere-butyl rae- (3R, 5R) -3-acetamido-3- (tere-butylcarbamoyl) -5-vinylpiperidine-1-carboxylate (see Comparative Example 57, step B, 0.5 g, 1.36 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred for one hour and then concentrated under reduced pressure to provide a crude product (1 g) as an orange liquid. The crude product was used in the next step without further purification. ESI + MS: m / z = 268.2 (M + 1) +.

1H NMR (700 MHz, Chloroform-d) 9.02 (bd, J = 11.2 Hz, 1H), 8.30 - 8.25 (m, 1H), 7.82 (s, 1H), 6 , 76 (s, 1H), 5.63 (ddd, J = 17.2, 10.5, 6.8 Hz, 1H), 5.26 (d, J = 10.4 Hz, 1H), 5, 19 (dd, J = 17.2, 1.2 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 3.48 - 3.43 (m, 1H), 2.96 - 2.84 (m, 2H), 2.64-2.57 (m, 1H), 2.30-2.24 (m, 1H), 2.09 (s, 3H), 1.84 (t , J = 13.1 Hz, 1H), 1.35 (s, 9H).

Step B. rae- (3R, 5R) -3-Acetamido-N- (tere-butyl) -1-methyl-5-vinylpiperidine-3-carboxamide

To the solution of rae- (3R, 5R) -3-acetamido-N- (tere-butyl) -5-vinylpiperidine-3-carboxamide trifluoroacetate (1 g, crude) in DCE (1.5 mL) was added formalin (0.5 mL). The mixture was stirred for 30 min, followed by the portionwise addition of NaBH (OAc) 3 (1.3 g, 6.13 mmol). After stirring overnight, the reaction mixture was diluted with DCM (70 mL), subsequently washed with NaOH (aq) (1 M, 2 x 10 mL), brine (10 mL), dried over MgsO4, and concentrated to provide 0.27 g (70%, after two steps) of the desired product as a white solid. ESI + MS: m / z = 282.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 59.47 (bs, 1H), 6.66 (s, 1H), 5.67 (ddd, J = 17.2, 10.4, 6.7 Hz, 1H ), 5.07 -5.01 (m, 2H), 3.07 (d, J = 11.5 Hz, 1H), 2.92 (d, J = 11.5, 1H), 2.83 ( dd, J = 10.7, 3.9 Hz, 1H), 2.55-2.50 (m, 1H), 2.33 (s, 3H), 2.14-2.05 (m, 1H) , 1.98 (d, J = 1.2 Hz, 3H), 1.95 (t, J = 11.3 Hz, 1H), 1.77 (ddd, J = 13.0, 4.1, 1 , 9Hz, 1H), 1.37 (s, 9H).

Step C. rac- (3R, 5S) -3-Acetamido-N- (tere-butyl) -1-methyl1-5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) ethyl) piperidine-3-carboxamide

The title compound was prepared from rae- (3R, 5R) -3-acetamido-N- (tere-butyl) -1-methyl-5-vinylpiperidine-3-carboxamide (0.26 g, 0.92 mmol ) using the procedure described for the preparation of Example 26, step B. The crude product was purified by flash chromatography on silica gel (DCM / acetone 50: 1 to 0: 1). Obtained: 0.28 g (74%) of the desired product (colorless oil) and 0.06 g of the product without pinacol (viscous white solid). ESI + MS: m / z = 410.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 59.51 (s, 1H), 6.62 (s, 1H), 2.98 (d, J = 11.4 Hz, 1H), 2.92 (dt, J = 11.4, 1.6 Hz, 1H), 2.86-2.80 (m, 1H), 2.29 (s, 3H), 1.96 (s, 3H), 1.85-1 , 70 (m, 4H), 1.34 (s, 9H), 1.37-1.30 (m, 2H), 1.24 (s, 12H), 0.82-0.69 (m, 2H ).

Step D. rae- (3R, 5S) -3-amino-5- (2-boronoethyl) -1-methylpiperidine-3-carboxylic acid

Title compounds were prepared from rae- (3R, 5S) -3-acetamido-N- (tere-butyl) -1-methyl-5- (2- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) ethyl) piperidine-3-carboxamide (100 mg, 0.24 mmol) using the procedure described for the preparation of Example 26, step C. The crude product was purified by preparative HPLC ( 0.1-1% MeCN in H2O) and then by Dowex 8x50. Obtained: 17 mg (30%) as a white solid. ESI + MS: m / z = 231.1 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.43 (d, J = 11.9 Hz, 1H), 3.40-3.33 (m, 1H), 2.83 (s, 3H), 2, 67 (d, J = 12.0 Hz, 1H), 2.53-2.49 (m, 1H), 2.06 (dd, J = 11.4, 1.7 Hz, 1H), 1.76 - 1.68 (m, 1H), 1.38-1.26 (m, 2H), 1.10 (t, J = 12.9 Hz, 1H), 0.75 - 0.65

(m, 2H).

Comparative Example 60. Rae- (3R, 5R) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid hydrochloride

Step A. 5-Vinyldihydro-2H-pyran-3 (4H) -one

The title compound 5-vinyldihydro-2H-pyran-3 (4H) -one was obtained in the same way as in step B from the synthesis of intermediate 1, using vinylmagnesium bromide (1M in THF) (10 , 2 mL, 10.2 mmol), HMPA (3.6 mL,

20.51 mmol), CuBr x Me2S (0.16 g, 0.76 mmol), 2H-Piran-3 (6H) -one (CAS number: 98166-23-5) (0.5g, 5.1 mmol ), TMSCl (3.2 mL, 25.5 mmol) and dry THF (20 mL + 8.5mL). The crude product was purified by silica gel flash chromatography (gradient elution, hexane / Et2O 100: 1 to 20: 1) to provide the corresponding product as a solution in a mixture of hexane / Et2O. The silica gel flash chromatography fractions were partially concentrated and used in the next step, because the desired product is volatile. 1H NMR (700 MHz, Chloroform-d) 55.77-5.76 (m, 2H), 5.23 -5.10 (m, 1H), 4.16-4.07 (m, 1H), 4 .02 (ddd, J = 10.9, 4.9, 0.8 Hz, 1H), 3.95 (d, J = 15.9 Hz, 1H), 3.56

(dd, J = 11.5, 8.9 Hz, 1H), 2.92-2.89 (m, 1H), 2.75-2.67 (m, 1H), 2.42 (dd, J = 16.1, 10.2 Hz, 1H).

Step B. rac- (3R, 5S) -3-Acetamido-N- (tert-butyl) -5-vinyltetrahydro-2H-pyran-3-carboxamide and rac- ( 3R, 5R) -3-acetamido-N- ( tert-butyl) -5-vinyltetrahydro-2H-pyran-3-carboxamide

The title compounds were obtained in the same way as in step C from the synthesis of intermediate 1, using a solution of 5-vinyldihydro-2H-pyran-3 (4H) -one in a mixture of hexane / Et2O, Ammonium acetate (4.84 mmol), tert-butylisocyanide (0.27 mL, 2.42 mmol) and 2,2,2-trifluoroethanol (5 mL) as a solvent. The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 1: 1) to provide the corresponding product as separable diastereoisomers (64 mg, 5% in two steps, white solid).

rac- (3R, 5S) -3-acetamido-N- (tert-butyl) -5-vinyltetrahydro-2H-pyran-3-carboxamide (14 mg, white solid); ESI + MS: m / z = 269.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.08 (s, 1H), 5.86 (s, 1H), 5.61 (ddd, J = 17.3, 10.5, 6.8 Hz, 1H ), 5.14-5.06 (m, 2H), 3.93-3.88 (m, 2H), 3.61 (d, J = 12.2 Hz, 1H), 3.15 (t, J = 11.3 Hz, 1H), 2.76-2.72 (m, 1H), 2.39 (dd, J = 11.2, 5.3 Hz, 1H), 2.10 (s, 3H ), 1.78 (dd, J = 13.6, 12.5 Hz, 1H), 1.34 (s, 9H).

rac- (3R, 5R) -3-acetamido-N- (tert-butyl) -5-v¡n¡ltetrahydro-2H-pyran-3-carboxamide (50 mg, white solid); ESI + MS: m / z = 269.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.37 (s, 1H), 6.40 (s, 1H), 5.62 ( ddd, J = 17.3, 10.5, 6.8 Hz, 1H), 5.14-5.08 (m, 2H), 4.24 (d, J = 11.8 Hz, 1H), 4.13-4.08 (m, 1H), 3.95 (dd, J = 11, 2, 3, 0 Hz, 1H), 3.31 (t, J = 11, 2 Hz, 1H),

2.65-2.52 (m, 1H), 2.33-2.26 (m, 1H), 1.99 (s, 3H), 1.98-1.95 (m, 1H), 1, 40 (s, 9H).

Step C. rac- (3R, 5R) -3-acetamide-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -d¡oxaborolan-2-¡l) eth¡l) tetrahydro-2H-pyran-3-carboxamide and rac- (3R, 5S) -3-acetamide-Ñ- (ferc-but¡l) - 5- (2- (4,4,5, 5-tetramethyl-1,3,2-d¡oxaborolan-2-¡l) ethyl) tetrahydro-2H-pyran-3-carboxam gives

The title compound rac- (3R, 5R) -3-acetamide-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-¡l) ethyl) tetrahydro-2H-pyran-3-carboxamide was obtained in the same manner as in Example 26, step B, using rac- (3R, 5S) -3-acetamide-N- (tert-butyl) -5-v¡n¡ltetrahydro-2H-pyran-3-carboxamide (14 mg, 0.052 mmol, 1 equ¡v.), Dppe (1 mg, 0.0031 mmol, 0.06 equ¡v.), B¡s dichloride (1,5-cyclooctadene) d¡¡r¡d ¡O (I) (1 mg, 0.0015 mmol, 0.03 equiv.), 4.4.5.5-tetramethyl-1,3,2-d¡oxaborolane (19 µl, 0.13 mmol, 2 , 5 equiv.) And DCM (2 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 100: 1 to 50: 1) to provide the corresponding product as a single diastereoisomer. co

(15 mg, 75%, sticky light yellow solid). ESI + MS: m / z = 397.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 57.15 (s, 1H), 5.79 (s, 1H), 3.93 (ddd, J = 26.9, 11.6, 2.8 Hz, 2H ), 3.58 (d, J = 12.1 Hz, 1H), 3.00 (t, J = 11.3 Hz, 1H), 2.69 (d, J = 14.2 Hz, 1H), 2.07 (s, 3H), 1.52-1.45 (m, 1H), 1.33 (s, 9H), 1.31-1.27 (m, 3H), 1.25 (s, 12H), 0.82-0.71 (m, 2H).

The title compound rac- (3R, 5S) -3-acetamide-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-¡l) ethyl) tetrahydro-2H-pyran-3-carboxamide was obtained in the same manner as in Example 26, step B, using rac- (3R, 5R) -3-acetamide-N- (tert-butyl) -5-v¡n¡ltetrahydro-2H-pyran-3-carboxamide (50 mg, 0.19 mmol, 1 equ¡v.), dppe (4 mg, 0.011 mmol, 0.06 equ¡v.), b¡s (1,5-cyclooctadene) d¡¡r¡d ¡O (l) (4 mg, 0.0055 mmol, 0.03 equiv.), 4.4.5.5-tetramethyl-1,3,2-dioxaborolane (68 µl, 0.46 mmol, 2 , 5 equiv.) And DCM (2ML). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 40: 1 to 10: 1) to provide the corresponding product as a single diastereoisomer. co

(50 mg, 67%, sticky light yellow solid). ESI + MS: m / z = 397.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-C) 57.38 (s, 1H), 6.41 (s, 1H), 4.21 (dd, J = 16.2, 11.7 Hz, 1H), 4, 12-4.06 (m, 1H), 4.02-3.94 (m, 1H), 3.12 (t, J = 12.0 Hz, 1H), 2.06-1.98 (m, 1H), 1.97 (s, 3H), 1.88-1.74 (m, 1H), 1.54 (d, J = 1.7 Hz, 1H), 1.38 (s, 9H), 1.37-1.33 (m, 1H), 1.25 (s, 12H), 1.23-1.15 (m, 1H), 0.82-0.68 (m, 2H).

Step D. Rac- (3R, 5R) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid hydrochloride

The title compound rac- (3R, 5R) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid hydrochloride is obtained in the same way as in Example 26, step C, using rac- (3R, 5R) -3-acetamid-N- (tert-butyl) -5- (2- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) tetrahydro-2H-pyran-3-carboxamide (15 mg, 0.037 mmol, 1 equiv.), HClac 6 N

(10 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification) Charge with 6N HCl and subsequent liofilization) a product as a single diastereoisomer (4.5 mg, 56%, white solid). ESI + MS: m / z = 218.1 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 54.01 - 3.97 (m, 1H), 3.82 (dd, J = 12.5, 2.5 Hz, 1H), 3.66 (d, J = 12.5 Hz, 1H), 3.11 (t, J = 11.2 Hz, 1H), 2.06-2.02 (m, 1H), 1.74 (q, J = 15.2, 14.0 Hz, 2H), 1.33-1.25 (m, 1H), 1.25-1.17 (m, 1H), 0.73 (ddd, J = 16.3, 10.4, 6.2 Hz, 1H), 0.68 (ddd, J = 15.7, 10.4, 6.3 Hz, 1H).

Comparative Example 61. Rac- (3R, 5S) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid hydrochloride co

The title compound rac- (3R, 5S) -3-amino-5- (2-boronoethyl) tetrahydro-2H-pyran-3-carboxylic acid hydrochloride is obtained in the same way as in Example 26, step C, using rac- (3R, 5S) -3-acetamid-N- (tert-butyl) -5- (2- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) tetrahydro-2H-pyran-3-carboxamide (40 mg, 0.10 mmol, 1 equiv.), HClac 6 N (10 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (10 mg, 45%, white solid). ESI + MS: m / z = 218.1 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 54.21 (dd, J = 11.6, 2.2 Hz, 1H), 3.94 (dd, J = 11.4, 3.2 Hz, 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.09 (t, J = 11.1 Hz, 1H), 2.42 (d, J = 17.3 Hz, 1H), 1, 96 -1.90 (m, 1H), 1.41

(dd, J = 13.2, 11.6 Hz, 1H), 1.32 (ddt, J = 13.7, 9.8, 6.8 Hz, 1H), 1.22 (ddt, J = 13 , 5, 10.1.6.7 Hz, 1H), 0.78-0.67 (m, 2H).

Comparative Example 62. 1,2-Diamino-4- (2-boronoethyl) cyclopentanecarboxylic acid dihydrochloride

Step A. Ethyl 2 - ((Diphenylmethylene) amino) pent-4-enoate

To the mixture of ethyl n- (diphenylmethylene) glycinate (20 g, 74.82 mmol), allyl bromide (7.1 mL, 82.30 mmol) and Cs2COs (53.6 g, 164.6 mmol) in Acetonitrile (500 mL) was added TBABr (2.4 g, 7.48 mmol). The reaction mixture was stirred at room temperature overnight. After that time, the reaction mixture was partitioned between water (250 mL) and AcOEt (300 mL). The layers were separated. The aqueous layer was washed with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (2 x 200 mL), brine (200 mL), dried over MgSO4, and concentrated in vacuo. The desired product was obtained as an orange oil (23.5 g). The crude product was used in the next reaction step without further purification. ESI + MS: m / z = 308.0 (M + 1) +. 1H NMR (700 MHz, Chloroform d) 87.68-7.64 (m, 2H), 7.48-7.44 (m, 3H), 7.43-7.39 (m, 1H), 7.37-7.33 ( m, 2H), 7.20 (dd, J = 7.4, 1.7 Hz, 2H), 5.71 (ddt, J = 17.1, 10.2, 7.1 Hz, 1H), 5.09 (dd, J = 17.1, 1.5 Hz, 1H), 5.04 (d, J = 10.2 Hz, 1H), 4.26 - 4.13 (m, 3H), 2.72 (dt, J = 12.2, 6.0 Hz, 1H), 2.65

(dt, J = 14.2, 7.6 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H).

Step B. Ethyl 2 - (((Benzyloxy) carbonyl) amino) pent-4-enoate

To the solution of ethyl 2- ((diphenylmethylene) amino) pent-4-enoate (22.9 g, 74.49 mmol) in THF (50 mL), 2N HClac (50 mL) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then washed with Et2O (6 x 50 mL). The aqueous residue was made alkaline with 5% NaHCO3 until pH = 8. Acetone (100 mL) was then added to the reaction mixture followed by the addition of Z-OSu (18.6g, 249.22 mmol). The resulting mixture was stirred at room temperature overnight. Acetone evaporated. The aqueous layer was acidified with 1N HClac and washed with DCM (2 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The desired product was obtained as an orange oil (20.04 g). The crude product was used in the next reaction step without further purification. ESI + MS: m / z = 277.9 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 87.38 (d, J = 4.7 Hz, 4H), 7.36 - 7.31 (m, 1H), 5.71 (td, J = 17.0 , 7.3 Hz, 1H), 5.34 (d, J = 4.9 Hz, 1H), 5.20 -5.10 (m, 4H), 4.46 (d, J = 7.3 Hz , 1H), 4.28-4.14 (m, 2H), 2.66-2.46 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H).

Step C. 2 - (((benzyloxy) carbonyl) amino) pent-4-enoic acid

The mixture of ethyl 2 - (((benzyloxy) carbonyl) amino) pent-4-enoate, ethanol (72 mL) and 4M NaOHac (20 mL) was stirred at room temperature for 4h. After that time, the ethanol was evaporated under reduced pressure and the aqueous layer was acidified with 1N HCl and washed with AcOEt (2 x 100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The desired product was obtained as a yellowish oil (17.3 g). The crude product was used in the next reaction step without further purification. ESI + MS: m / z = 248.05 (M-1) '. 1H NMR (700 MHz, Chloroform- d ) 87.38

(d, J = 5.1 Hz, 4H), 7.36 - 7.31 (m, 1H), 5.74 (dq, J = 17.0, 7.2 Hz, 1H), 5.31 ( p, J = 9.2 Hz, 1H), 5.22 -5.11 (m, 4H), 4.51 (q, J = 6.5, 6.0 Hz, 1H), 2.62 (ddt , J = 50.4, 15.2, 6.8 Hz, 2H).

Step D. Benzyl (1- (Methoxy (methyl) amino) -1-oxopent-4-en-2-yl) carbamate

To the solution of 2 - (((benzyloxy) carbonyl) amino) pent-4-enoic acid (17.2 g, 68.99 mmol, crude) in DCM (170 mL) was added N, O-dimethylhydroxylamine hydrochloride ( 7.07 g, 72.44 mmol) and DIPEA (24.8 mL, 144.87 mmol). HATU (27.54 g, 72.44 mmol) was then added to the reaction mixture and stirred at room temperature overnight. After that time, the mixture was diluted with DCM and washed with 1N HCl (2 x 100 mL), 1N NaOH (2 x 100 mL), brine (1 x 100 mL), dried over MgSO4 and concentrated in vacuo . The desired product was crystallized from AcOEt / hexane to provide the pure product (14.69 g, 67% in 5 steps, white solid). ESI + MS: m / z = 293.0 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 87.37 (d, J = 5.4 Hz, 4H), 7.35 - 7.31 (m, 1H), 5.77 (td, J = 17.2 , 7.2 Hz, 1H), 5.47 (d, J = 10.4 Hz, 1H), 5.15-5.09 (m, 4H), 4.84 (s, 1H), 3.81 (s, 3H), 3.23 (s, 3H), 2.54 (dt, J = 12.9, 6.1 Hz, 1H), 2.42 (dt, J = 14.1, 7.1 Hz, 1H).

Step E. Benzyl (3-Oxohepta-1,6-dien-4-yl) carbamate

To a solution of benzyl (1- (methoxy (methyl) amino) -1-oxopent-4-en-2-yl) carbamate (5 g, 17.11 mmol) in dry THF

(100 mL) A solution of 1M vinyl magnesium bromide in THF (60 mL, 59.87 mmol) was added dropwise at -78 ° C under argon. The reaction mixture was stirred at -78 ° C to 0 ° C for 3h. The mixture was cooled once more to -78 ° C and poured into a cold 2N HCl solution. The aqueous layer was extracted with AcOEt (2 x 100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 3: 1) to provide the corresponding product (3.14 g, 71%, white solid). ESI + MS: m / z = 282.0 (M + Na) +. 1H NMR (700 Mh z, Chloroform-cf) 7.40 - 7.36 (m, 4H), 7.34 (td, J = 8.4, 3.7 Hz, 1H), 6.52 (dd , J = 17.5, 10.5 Hz, 1H), 6.42 (d, J = 17.3 Hz, 1H), 5.93 (d, J = 10.6 Hz, 1H), 5.66 (td, J = 17.2, 7.2 Hz, 1H), 5.58 (d, J = 8.2 Hz, 1H), 5.16 -5.08 (m, 4H), 4.80 - 4.71 (m, 1H), 2.71-2.66 (m, 1H), 2.45 (dt, J = 13.8, 6.6 Hz, 1H).

Step F. Benzyl (2-Oxocyclopent-3-en-1-yl) carbamate

To the solution of benzyl (3-oxohepta-1,6-dien-4-yl) carbamate (4.1g, 15.81 mmol) in DCM (850 mL) under argon was added Grubbs Catalyst, 2nd Generation ( 0.67g, 0.79mmol). The reaction mixture was stirred at room temperature overnight. After that time, the solvent was evaporated and the residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 10: 1 to 3: 1) to provide the corresponding product (3.03 g, 84% , off-white solid). ESI + MS: m / z = 254.0 (M + Na) +. 1H Rm N (700 MHz, Chloroform-cf) 5 7.71 (s, 1H), 7.38 (d, J = 5.6 Hz, 4H), 7.34 (dd, J = 9.7, 4 , 6Hz, 1H), 6.28 (d, J = 5.0Hz, 1H), 5.28 (s, 1H), 5.18-5.12 (m, 2H), 4.10 (s , 1H), 3.25 (d, J = 20.7Hz, 1H), 2.68 (d, J = 17.8Hz, 1H).

Step G. Benzyl (2-Oxo-4-vinylcyclopentyl) carbamate

The title compound (2-oxo-4-vinylcyclopentyl) benzyl carbamate was obtained in the same way as in Comparative Example 57, step A, using benzyl (2-oxocyclopent-3-en-1-yl) carbamate ( 3 g, 12.97 mmol), vinylmagnesium bromide (1 M in THF) (45.41 mL, 45.41 mmol), HMPA (9 mL, 51.90 mmol), CuBr x Me2S (0.4 g, 1.95 mmol) and TMSCl (8.2 mL, 64.86 mmol), dry THF (62 mL + 31 mL). The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 100: 1 to 5: 1) to provide the corresponding product as a mixture of diastereoisomers, dr = 1: 1, (2.72 g , 81%, white solid). ESI + MS: m / z = 260.0 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 57.41 - 7.36 (m, 4H), 7.36 - 7.31 (m, 1H), 6.01 -5.78 (m, 1H), 5 , 26-5.06 (m, 5H), 4.11-4.02 (m, 1H), 3.09-2.70

(m, 1H), 2.66-2.39 (m, 2H), 2.11-1.95 (m, 1H), 1.59-1.53 (m, 1H).

Step H. Benzyl (2-Acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) carbamate

The title compound (2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) benzyl carbamate was obtained in the same way as in step C from the synthesis of intermediate 1, using (2-oxo- Benzyl 4-vinylcyclopentyl) carbamate

(2.65 g, 10.03 mmol, 1 equiv.), Ammonium acetate (3.15 g, 40.93 mol, 4 equiv.), Tert-butylisocyanide (2.3 mL, 20.07 mol, 2 equiv.) and 2,2,2-trifluoroethanol (36 mL) as a solvent. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 100: 1 to 1: 1) to provide the corresponding product as a mixture of partially separable diastereoisomers (2.36 g, 57%, white solids ). The first diastereoisomer: (0.34 g, white solid); ESI + MS: m / z = 402.1 (M + 1) +. 1H Rm N (700 MHz, Chloroform-cf) 5 7.48 (s, 1H), 7.37 (s, 4H), 7.36 - 7.31 (m, 2H), 5.87 (d, J = 9.2 Hz, 1H), 5.79 (ddd, J = 17.2, 10.2, 7.2 Hz, 1H), 5.19 -5.10 (m, 2H), 5.00 ( d, J = 17.1 Hz, 1H), 4.98 - 4.93 (m, 1H), 4.15 (d, J = 10.1 Hz, 1H), 3.03 (dd, J = 13 , 6.7 Hz, 1H), 2.84 (s, 1H), 2.14-2.05 (m, 1H), 2.03 (s, 3H), 1.94-1.87 ( m, 1H), 1.73-1.67 (m, 1H), 1.31 (s, 9H).

Mixture of the second and third diastereoisomers: dr = 1: 1, (1.61 g, white solid); ESI + MS: m / z = 402.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 7.40 - 7.36 (m, 4H), 7.34 (dd, J = 7.4, 3.7 Hz, 1H), 7.16, 6, 96 [(2s, 1H, two diastereoisomers)], 6.91-6.66 (m, 1H), 5.88 -5.76 (m, 1H), 5.54 -5.13 (m, 2H) , 5.12-4.92 (m, 3H), 4.37-4.00 (m, 1H), 2.76-2.42 (m, 2H), 2.36-2.17 (m, 2H), 2.05, 1.90 [(2s, 3H, two diastereoisomers)], 1.96-1.85 (m, 1H), 1.37, 1.28 [(2s, 9H, two diastereoisomers) ].

The fourth diastereoisomer: (0.43 g, white solid); ESI + MS: m / z = 402.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 7.50-7.41 (m, 1H), 7.40-7.33 (m, 5H), 7.19-7.07 (m, 1H), 5.84 (ddd, J = 17.1, 10.3, 6.7 Hz, 1H), 5.39 -5.34 (m, 1H), 5.14 (d, J = 12.2 Hz, 1H), 5.12-5.06 (m, 2H), 5.03 (d, J = 10.3 Hz, 1H), 4.28 (d, J = 8.0 Hz, 1H), 2, 90-2.83 (m, 1H), 2.68

(dd, J = 14.0, 8.7 Hz, 1H), 2.49-2.42 (m, 1H), 2.08-2.02 (m, 1H), 1.98 (s, 4H ), 1.34 (s, 9H).

Step I. (2-Acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) carbamate benzyl

The first diastereoisomer of the title compound (2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) Benzyl cyclopentyl) carbamate was obtained in the same way as in Example 26, step B, using (2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) carbamate (0.34 g, 0.85 mmol, 1 equiv.), Dppe (20 mg, 0.05 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (17 mg, 0.025 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.31 mL, 2.12 mmol 2.5 equiv.) And d Cm (10 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 100: 1 to 50: 1) to provide the corresponding one as a single diastereoisomer (0.37 g, 82%, white solid). ESI + MS: m / z = 530.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 57.59 (s, 1H), 7.40-7.31 (m, 6H), 5.92 (d, J = 9.2 Hz, 1H), 5, 20 -5.09 (m, 2H), 4.14-4.02 (m, 1H), 2.98 (dd, J = 13.4, 7.4 Hz, 1H), 2.13-2, 06 (m, 1H), 2.00 (s, 4H), 1.75-1.70 (m, 1H), 1.50-1.40 (m, 3H), 1.30 (s, 9H) , 1.25 (s, 12H), 0.76 (t, J = 8.1 Hz, 2H).

The second and third diastereoisomers of the title compound (2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl Benzyl) ethyl) cyclopentyl) carbamate were obtained in the same way as in Example 26, step B, using (2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) carbamate (0.59 g, 1, 47 mmol, 1 equiv.), Dppe (35 mg, 0.088 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (30 mg, 0.044 mmol, 0.03 equiv.) , 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 3.68 mmol, 2.5 equiv.) And DCM (28mL). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 10: 1 to 1: 1) to provide the corresponding product as a mixture of separable diastereoisomers (0.44g, 56%, white solid , sticky).

Second diastereoisomer: (0.10 g, white solid); ESI + MS: m / z = 530.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-cf) 7.40 - 7.33 (m, 6H), 7.15 (s, 1H), 6.84 (s, 1H), 5.58 (d, J = 6.9Hz, 1H), 5.16 (d, J = 12.2Hz, 1H), 5.11-5.08 (m, 1H), 4.18-4.10 (m, 1H), 4.02-3.94 (m, 1H), 2.45-2.39 (m, 1H), 2.27-2.21 (m, 1H), 2.03 (s, 3H), 2, 01-1.96 (m, 1H), 1.68-1.60 (m, 1H), 1.51 (d, J = 2.7 Hz, 1H), 1.28 (s, 9H), 1 , 24 (s, 12H), 0.78-0.74 (m, 2H).

The third diastereoisomer: (40 mg, white solid); ESI + MS: m / z = 530.3 (M + 1) +. 1H NMR (700MHz, Chloroform-cf) 7.39-7.31 (m, 6H), 7.17-7.06 (m, 1H), 6.87-6.71 (m, 1H), 5.14 (d, J = 12.3 Hz, 1H), 5.10 -5.05 (m, 1H), 4.29 (q, J = 10.4, 9.2 Hz, 1H), 2 , 40-2.34 (m, 1H), 2.33-2.27 (m, 1H), 2.02-1.96 (m, 1H), 1.90 (s, 3H), 1.87 - 1.80 (m, 1H), 1.72 (dt, J = 12.6, 9.9 Hz, 1H), 1.52-1.47 (m, 2H), 1.36 (s, 9H ), 1.25 (s, 12H), 0.79 (t, J = 8.1 Hz, 2H).

The fourth diastereoisomer of the title compound (2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) Benzyl cyidopentyl) carbamate was obtained in the same manner as in Example 26, step B, using (2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) carbamate (0.43 g, 10.72 mmol, 1 equiv.), Dppe (26 mg, 0.064 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (22 mg, 0.032 mmol, 0.03 equiv.), 4, 4,5,5-tetramethyl-1,3,2-dioxaborolane (0.39 mL, 26.81 mmol, 2.5 equiv.) And DCM (21 mL). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 50: 1 to 1: 1) to provide the corresponding product as a single diastereoisomer (0.43 mg, 76%, off-white solid, sticky). ESI + MS: m / z = 530.3 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 67.44 - 7.36 (m, 6H), 7.36 - 7.32 (m, 1H), 5.54 -5.41 (m, 1H), 5 , 14

(d, J = 12.3 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 4.19 (q, J = 7.4 Hz, 1H), 2.55 (dd , J = 13.8, 8.3 Hz, 1H), 2.31 (dt, J = 13.9, 6.9 Hz, 1H), 2.15-2.03 (m, 1H), 1, 97 (s, 3H), 1.79-1.69 (m, 2H), 1.49-1.45 (m, 2H), 1.33 (s, 9H), 1.25 (s, 12H) ,

0.78 - 0.72 (m, 2H).

Step J. 1,2-Diamino-4- (2-boronoethyl) cyclopentanecarboxylic acid dihydrochloride

The first diastereoisomer of the title compound 1,2-diamino-4- (2-boronoethyl) cyclopentanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26, step C, using (2-acetamido-2- (ferc- benzyl butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) carbamate (60 mg, 0.11 mmol, 1 equiv. ), 6N HClac (15 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (15.4 mg, 47%, white solid). ESI + MS: m / z = 217.1 (M + 1) +. 1H Rm N (700 MHz, Deuterium Oxide) 63.92 (dd, J = 9.2, 5.5 Hz, 1H), 2.54 (dd, J = 13.7, 6.6 Hz, 1H) , 2.34 (dt, J = 15.9, 8.3 Hz, 1H), 2.15-2.09 (m, 1H), 1.99 (dt, J = 14.2, 9.0 Hz , 1 HOUR),

I, 65 (dd, J = 13.7, 10.5 Hz, 1H), 1.47-1.41 (m, 2H), 0.74-0.69 (m, 2H).

The second diastereoisomer of the title compound 1,2-diamino-4- (2-boronoethyl) cyclopentanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26, step C, using (2-acetamido-2- (ferc- benzyl butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) carbamate (54 mg, 0.10 mmol, 1 equiv. ), 6N HClac (15 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (10.55 mg, 36%, white solid). ESI + MS: m / z = 217.1 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 63.77 (dd, J = 10.9, 7.1 Hz, 1H), 2.42 (dt, J = 12.8, 6.3 Hz, 1H), 2.23 (dd, J = 13.3, 6.3 Hz, 1H), 2.11 (dt, J = II, 6, 6.2 Hz, 1H), 2.05

(dd, J = 14.0, 11.3 Hz, 1H), 1.68-1.60 (m, 1H), 1.47 (dq, J = 14.1, 7.1, 6.2 Hz , 2H), 0.73 (t, J = 8.1 Hz, 2H).

The third diastereoisomer of the title compound 1,2-diamino-4- (2-boronoethyl) cyclopentanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26, step C, using (2-acetamido-2- (ferc- benzyl butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) carbamate (30 mg,

0.056 mmol, 1 equiv.), 6N HClac (10 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (6.6 mg, 41%, white solid). ESI + MS: m / z = 217.1 (M + 1) +. 1H Rm N (700 MHz, Deuterium Oxide) 64.11 (dd, J = 12.7, 6.4 Hz, 1H), 2.57 (dd, J = 14.9, 9.1 Hz, 1H) , 2.41 (dt, J = 12.4, 6.3 Hz, 1H), 2.14 - 2.05 (m, 1H), 1.64 (dd, J = 14.9, 9.5 Hz , 1H), 1.54 (q, J = 12.4 Hz, 1H), 1.51-1.43 (m, 2H), 0.74 (t, J = 8.2 Hz, 2H).

The fourth diastereoisomer of the title compound 1,2-diamino-4- (2-boronoethyl) cyclopentanecarboxylic acid dihydrochloride was obtained in the same manner as in Example 26, step C, using (2-acetamido-2- (ferc- benzyl butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) carbamate (60 mg,

0.11 mmol, 1 equiv.), 6N HClac (15 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) a product as a single diastereoisomer (9.2 mg, 28%, white solid). ESI + MS: m / z = 217.1 (M + 1) +. 1H Rm N (700 MHz, Deuterium Oxide) 64.26 - 4.16 (m, 1H), 2.33 - 2.20 (m, 2H), 2.12 - 2.01 (m, 2H), 2.02-1.95 (m, 1H), 1.55-1.41 (m, 2H), 0.71 (t, J = 8.1 Hz, 2H).

Comparative Example 63. 1-Amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid hydrochloride

Step A. 2-Oxo-4-vinylcyclopentyl acetate

The title compound 2-oxo-4-vinylcyclopentyl acetate was obtained in the same way as in step B from the synthesis of intermediate 1, using 2-oxocyclopent-3-en-1-yl acetate (2, 5 g, 17.80 mmol, 1 equiv.), Vinylmagnesium bromide (1 M in THF) (35.6 mL, 35.56 mmol, 2 equiv.), HMPA (12.4 mL, 71.36 mmol, 4 equiv.), CuBr x Me2S

(0.55 g, 2.67 mmol, 0.15 equiv.), And TMSCl (11.3 mL, 89.0 mmol, 5 equiv.), Dry THF (140 mL + 40mL). The crude product was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 200: 1 to 20: 1) to provide the corresponding product 2-oxo-4-vinylcyclopentyl acetate as a mixture of diastereoisomers.

dr = 9: 1 (2.1g 67%, yellow oil). 1H NMR (700 MHz, Chloroform-d) 55.90, 5.82 [(2ddd, J = 17.0, 10.4, 6.3 Hz, J = 17.1, 10.2, 6.8 Hz , 1H, two diastereoisomers)], 5.16-5.03 (m, 2H), 3.14-2.98 (m, 1H), 2.55 (dd, J = 18.7, 8.4 Hz , 1H), 2.35-2.23 (m, 2H), 2.18-2.12 (m, 1H), 2.11 (s, 3H), 1.35-1.22 (m, 1H ).

Step B. 2-Acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclopentyl acetate

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl acetate as a mixture of diastereoisomers was obtained in the same way as in step C from the synthesis of intermediate 1, using an acetate of 2-oxo-4-vinylcyclopentyl (1.9 g, 11.30 mmol, 1 equiv.), Ammonium acetate (3.48 g, 45.20 mmol, 4 equiv.), Tert-butylisocyanide (2.5 mL , 22.60 mmol, 2 equiv.) And 2,2,2-trifluoroethanol (3.1 mL) as a solvent. The residue was purified by silica gel flash chromatography (gradient elution, hexane / AcOEt 20: 1 to 1: 2) to provide the product 2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl acetate as a mixture of four diastereoisomers (1.65g, 47%, yellow solid).

First diastereoisomer:

Single diastereoisomer (0.92g, yellow solid) ESI + MS: m / z = 311.3 (M + 1) +, 333.3 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 56.64 (br s, 1H), 6.37 (br s, 1H), 5.88 -5.76 (m, 1H), 5.08 - 4.91 (m, 1H), 3.16 (dd, J = 14.3, 9.1 Hz, 1H), 3.10-3.03 (m, 1H), 2.22 (ddd, J = 13.7 , 9.1.6.6 Hz, 1H), 2.08 (s, 2H), 2.00 (s, 2H), 1.95 (ddd, J = 13.4, 7.0, 5.9 Hz, 1H), 1.68 (dd, J = 14.3, 6.7 Hz, 1H), 1.55 (s, 8H), 1.53-1.50 (m, 1H).

Second diastereoisomer:

Single diastereoisomer (0.37g, yellow solid) ESI + MS: m / z = 311.3 (M + 1) +, 333.3 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 56.64 (s, 1H), 6.37 (s, 1H), 5.81 (ddd, J = 17.1, 10.3, 6.9 Hz, 1H ), 5.10-4.90 (m, 2H), 3.16

(dd, J = 14.3, 9.1 Hz, 1H), 3.07 (dt, J = 15.8, 7.9 Hz, 1H), 2.22 (ddd, J = 13.7, 9 , 1.6.6 Hz, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.95 (ddd, J = 13.4, 7.0, 5.9 Hz, 1H), 1.68 (dd, J = 14.3, 6.7 Hz, 1H), 1.55 (s, 9H), 1.52-1.51 (m, 1H).

The first and third diastereoisomers:

Mixture of diastereoisomers, dr = 4: 3, (0.24g, yellow solid) ESI + MS: m / z = 311.3 (M + 1) +, 333.4 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 56.64, 6.61 [(2s, 1H, two diastereoisomers)], 6.37, 6.18 [(2s, 1H, two diastereoisomers)], 5.87, 5.81 [(2ddd, J = 17.2, 10.2, 7.4 Hz, J = 17.2, 10.3, 6.9 Hz, 1H, two diastereoisomers)], 5.08-4, 95 [(m, 2H, two diastereoisomers)], 3.16, 2.64 [(2dd, J = 14.3, 9.2 Hz, J = 14.5, 10.2 Hz, 1H, two diastereoisomers) ], 3.12-2.68 [(m, 1H, two diastereoisomers)], 2.27-2.18 (m, 1H), 2.08, 2.07 [(2s, 3h, two diastereoisomers)] 2.02, 2.00 [(s, 3h, two diastereoisomers)], 1.97-1.86 (m, 1H), 1.68 (dd, J = 14.3, 6.7 Hz, 1H) , 1.52-1.49 (m, 1H), 1.32 (s, 8H).

The first, the second, the third, the fourth diastereoisomers:

Mixture of 1st, 2nd, 3rd and 4th diastereoisomers 1: 1: 4: 4 (0.12g, yellow solid). ESI + MS: m / z = 311.3 (M + 1) +, 333.3 (M + Na) +.

1H NMR (700 MHz, Chloroform-d) 57.16, 7,11,6,64, 6.61 [(4s, 1H, four diastereoisomers)], 6.18 (s, 1H), 5.81

(dddd, J = 89.1, 17.2, 10.2, 7.1 Hz, 1H), 5.16-4.82 (m, 2H), 2.79-2.57 (m, 2H) , 2.49-2.41 (m, 1H), 2.23-2.18 (m, 1H), 2.11, 2.10, 2.08, 2.07 [(4s, 3H, four diastereoisomers )], 2.05, 2.04, 2.02, 2.00 [(4s, 3H, four diastereoisomers)],

1.52-1.51 (m, 2H), 1.32 (s, 9H).

Step C. 2-Acetamido-2- (cer-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl acetate

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl acetate as A single 1st diastereoisomer was obtained in the same manner as in Example 26, step B, using 2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl acetate (0.92 g, 2.96 mmol, 1 equiv .), dppe (0.071 g, 0.18 mmol, 0.06 equiv.), bis (1,5-cyclooctadiene) diiridium (I) dichloride (0.06 g, 0.089 mmol, 0.03 equiv.),

4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.56 mL, 3.85 mmol, 1.3 equiv.). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 20: 1 to 1: 2) to provide the corresponding product 2-acetamido-2- (fe / 'c-butylcarbamoyl) acetate -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a single diastereoisomer (1.26g, 97%, light yellow solid). ESI + MS: m / z = 439.5 (M + 1) +, 461.4 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 56.75 (br s, 1H), 6.44 (br s, 1H), 3.04 (dd, J = 14.4, 9.2 Hz, 1H), 2.29 (hept, J = 7.8 Hz, 1H), 2.13 (ddd, J = 13.7, 9.2, 6.5 Hz, 1H), 2.06 (s, 3H), 1 , 99 (s, 3H), 1.76 (dd, J = 13.9, 6.6 Hz, 1H), 1.50-1.42 (m, 3H), 1.31 (s, 8H), 1.26-1.25 (m, 1H), 1.24 (s, 11H), 1.24-1.22 (m, 1H), 0.81-0.70 (m, 2H).

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl acetate is obtained in the same manner as in Example 26, step B, using 2-acetamido-2- (ert-butylcarbamoyl) -4-vinylcyclopentyl acetate (2nd single diastereoisomer) (0.36 g, 1.71 mmol, 1 equiv .), dppe (0.041 g, 0.10 mmol,

0.06 equiv.), Bis (1,5-cidooctadiene) diiridium (I) dichloride (0.034 g, 0.051 mimols, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2 -dioxaborolane (0.32 mL, 2.22 mimols, 1.3 equiv.). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 20: 1 to 1: 5) to provide the corresponding product acetate of

2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a mixture of diastereoisomers dr = 4: 1 (0.48g, 64%, light yellow solid). ESI + MS: m / z = 439.5 (M + 1) +, 461.4 (M + Na) +. 1H NMR

(700 MHz, Chloroform-d) 67.17 (s, 1H), 6.18, 6.09 [(2s, 1H, two diastereoisomers)], 5.57 -5.47 (m, 1H), 2, 73, 2.58 [(2dd, J = 13.7, 8.0 Hz, J = 13.5, 8.0 Hz, 1H, two diastereoisomers)], 2.08 (s, 3H), 2.06 , 2.02 [(2s, 3H, two diastereoisomers)],

1.96-1.86 (m, 1H), 1.79-1.72 (m, 2H), 1.50-1.41 (m, 2H), 1.31, 1.30 [(2s, 9H, two diastereoisomers)], 1.24 (d, J = 1.8 Hz, 1H), 1.23 (d, J = 1.7 Hz, 3H), 1.23 (br s, 9H), 0 , 73 (dt, J = 13.5, 8.1 Hz, 2H).

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl acetate is obtained in the same way as in Example 26, step B, using 2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl acetate as a mixture of diastereoisomers (1st and 3rd diastereoisomers dr = 4: 3) (0 , 24 g,

0.77 mmol, 1 equiv.), Dppe (0.018 g, 0.046 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (0.016 g,

0.023 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 mL, 1.00 mmol 1.3 equiv.). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 20: 1 to 1: 2) to provide the corresponding product 2-acetamido-2- (tert-butylcarbamoyl) -4- acetate (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a mixture of three diastereoisomers dr = 5: 4: 1 (0.27g, 80%, light yellow solid). ESI + MS: m / z = 439.4 (M + 1) +, 461.4 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 66.76, 6.75, 6.50, [(3s, 1H, three diastereoisomers)], 6.44, 6.30, 6.28 [(3s, 1H, three diastereoisomers)], 3.09, 3.04, 2.40 [(3dd, J = 14.2, 8.84, J = 14.4, 9.2 Hz, J = 14.4, 10.1 Hz, 1H, three diastereoisomers)], 2.32-2.23 (m, 1H), 2.20-2.08 (m, 2H), 2.05, 2.04, 2.02 [(3s, 3H, three diastereoisomers)], 2.01, 2.00, 1.99 [(3s, 3H, three diastereoisomers)], 1.75-1.30 (m, 1H), 1.68-1.60 ( m, 1H), 1.54-1.51 (m, 1H), 1.49-1.44 (m, 2H), 1.32, 1.31.1.30 [(3s, 9H, three diastereoisomers ), 1.24 (br s, 8H), 1.23 (br s, 2H), 0.91-0.73 (m, 3H).

The title compound 2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl acetate is obtained in the same way as in Example 26, step B, using 2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl acetate (1st, 2nd, 3rd and 4th diastereoisomers 1: 1: 4: 4) ( 0.12 g, 0.39 mmol, 1 equiv.), Dppe (0.009 g, 0.023 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (0.008 g, 0.012 mmol , 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.07 mL, 0.50 mmol, 1.3 equiv.). The crude product was purified by silica gel column chromatography (gradient elution, hexane / AcOEt 20: 1 to 1: 2) to provide the corresponding product 2-acetamido-2- (tert-butylcarbamoyl) -4- acetate (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a mixture of four diastereoisomers dr = 10: 8: 1: 1 (0.14g, 82 %, colorless film). ESI + MS: m / z = 439.5 (M + 1) +, 461.4 (M + Na) +. 1H NMR (700 MHz, Chloroform-d) 6 7.17, 6.75, 6.56, 6.49 [(4s, 1H, four diastereoisomers)], 6.44, 6.29, 6.186.09 [( 4s, 1H, four diastereoisomers)], 2.58 (dd, J = 13.5, 7.9 Hz, 1H), 2.45-2.35 (m, 1H), 2.18-2.09 ( m, 1H), 2.08, 2.06, 2.05, 2.05 [(s, 3H four diastereoisomers)], 2.02, 2.01.2.00, 1.99 [(4s, 3H four diastereoisomers)], 1.98-1.92 (m, 1H), 1.88 (dd, J = 13.5, 9.0 Hz, 1H), 1.68-1.60 (m, 1H) , 1.56 (q, J = 8.0 Hz, 1H), 1.51-1.49 (m, 2H), 1.49-1.42 (m, 2H), 1.37-1.33 (m, 1H), 1.31 (dd, J = 3.6, 2.1 Hz, 6H), 1.27, 1.24, 1.24, 1.23 [(4s, 9H, four diastereoisomers) ], 1.26-1.25 (m, 1H), 0.9-0.74 (m, 3H).

Step D. 1-Amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid hydrochloride

The title compound 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid hydrochloride was obtained in the same way as in Example 26, step C, using the compound 2-acetamido-2- (fercbutylcarbamoyl acetate ) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a single 1st diastereoisomer (1.24g, 2.83mmol,

1 equiv.), 6N HClac (10 mL). The residue was purified by preparative HPLC (0.1-1% MeCN in water) and then by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidify with 6N HCl and subsequent lyophilization) the hydrochloride product of 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid as a mixture of diastereoisomers dr = 9: 1 (0.50g, 70%, white solid). ESI + MS: m / z = 218.2 (M + 1) +. ESI-MS: m / z = 216.0 (M-1) -, 198.0 (M-H2O-1) -. 1H NMR (700 MHz, Deuterium Oxide) 64.43-4.3 [(m, 1H, two diastereoisomers)], 2.57 (dd, J = 14.0, 8.0 Hz, 1H), 2, 34 (p, J = 8.5 Hz, 1H), 2.03 (dt, J = 14.7, 7.7 Hz, 1H), 1.90-1.71 (m, 1H), 1.51 - 1.37 (m, 3H), 0.72 (td, J = 7.5, 1.6 Hz, 2H).

The title compound 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid hydrochloride was obtained in the same way as in Example 26, step C, using the compound 2-acetamido-2- (fercbutylcarbamoyl acetate ) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a mixture of 4: 1 diastereoisomers (0.47g,

1.07 mimols, 1 equiv.), 6N HClac (8 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) the hydrochloride product of 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid as a mixture of diastereoisomers dr = 4: 1 (0.14g, 50%, white solid). ESI + MS: m / z = 218.3 (M + 1) +. ESI-MS: m / z = 216.0 (M-1) -, 198.0 (M-H2O-1) -. 1H NMR (700 MHz, Deuterium Oxide) 84.51, 4.45 [(t, J = 6.8 Hz, dd, J = 10.6, 6.5 Hz, 1H, two diastereoisomers)], 2, 46, 2.11 [(2dd, J = 14.6, 8.0 Hz, J = 14.5, 7.5 Hz, 1H, two diastereoisomers)], 2.26, 2.16 [(2dt, J = 13.0, 6.5 Hz, J = 15.9, 8.1 Hz, 1H), 1.88 (dd, J = 14.5, 9.2 Hz, 1H), 1.83 (td, J = 7.7, 3.7 Hz, 2H), 1.54-1.27 [(m, 2H, two diastereoisomers)], 0.72 (td, J = 8.7, 8.0, 4, 2Hz, 2H).

The title compound 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid hydrochloride was obtained in the same way as in Example 26, step C, using the compound 2-acetamido-2- (fercbutylcarbamoyl acetate ) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a mixture of three diastereoisomers 5: 4: 1 (0.27g,

0.62 mmol,

1 equiv.), 6N HClac (5 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidify with 6N HCl and subsequent lyophilization) the hydrochloride product of 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid as a mixture of diastereoisomers dr = 5: 4: 1 (0.11g, 74%, white solid ). ESI + MS: m / z = 218.3 (M + 1) +. ESI-MS: m / z = 216.0 (M-1) -, 198.0 (M-H2O-1) -. 1H NMR (700 MHz, Deuterium Oxide) 84.52-4.27 [(m, 1H, three diastereoisomers)], 2.61-2.24 [(m, 1H, three diastereoisomers)], 2.23- 2.11 (m, 1H), 2.06-1.94 (m, 1H), 1.88-1.57

[(m, 1H, three diastereoisomers)], 1.54-1.27 (m, 3H), 0.72 (t, J = 8.1 Hz, 2H).

The title compound 1-amino-4- (2-boronoethyl) -2-hydroxycyclopentanecarboxylic acid hydrochloride was obtained in the same way as in Example 26, step C, using the compound 2-acetamido-2- (tert- butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl as a mixture of four diastereoisomers 4: 4: 1: 1 (0, 14g, 0.32mmol, 1 equiv.), 6N HClac (5 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with 6N HCl and subsequent lyophilization) the 1-amino-4- acid hydrochloride product ( 2-boronoethyl) -2-hydroxycyclopentanecarboxylic as a mixture of diastereoisomers dr = 10: 8: 1: 1 (0.09g, 100%, white solid). ESI + MS: m / z = 218.2 (M + 1) +. ESI-MS: m / z = 216.0 (M-1) -, 198.0 (M-H2O-1) -. 1H NMR (700 MHz, Deuterium Oxide) 8 4.63 - 4.16 [(m, 1H, four diastereoisomers)], 2.63 - 2.25

[(m, 1H, four diastereoisomers)], 2.27-2.11 (m, 1H), 2.09-1.60 (m, 2H), 1.53-1.29 (m, 3H), 0.90 - 0.63 (m, 2H).

Comparative Example 64. Rac- (1R, 5R) -1-amino-5- (2-boronoethyl) -2- (dimethylamino) cyclohexane-1-carboxylic acid dihydrochloride

Step A. Rac- (2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylic acid.

To a solution of rac- (1R, 2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate (Intermediate 1, 2g, 5.91 mmol, 1 equiv.) In methanol (20 mL) 1N NaOH (2 mL) and 4N NaOH (2 mL) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was dissolved in H2O and washed with diethyl ether. The aqueous layer was then acidified with 6N HCl until pH = 2. The solid was filtered off and dried in vacuo to provide the corresponding product as a mixture of epimers, dr = 7: 3 (1.64 g, 90% , white solid). ESI + MS: m / z = 311.0 (M + 1) +; ESI-MS: m / z = 309.0 (M-1) \ 1H NMR (700 MHz, Chloroform-d) 8.32, 7.81 [(2s, 1H, two epimers)], 7.02, 6.19 [(2s, 1H, two epimers)], 5.78 -5.66 (m, 1H), 5.07-4.94 (m, 2H), 3.29-2.83 (m, 1H, two epimers), 2.81-2.39 (m, 1H, two epimers), 2.32-2.12 (m, 2H), 2.07, 2.03 [(2s, 3H, two epimers) )], 1.96-1.85 (m, 2H), 1.36, 1.35 [(2s, 9H, two epimers)], 1.33-1.13 (m, 2H).

Step B. rac-N - ((4aR, 6R) -3- (tert-Butyl) -2,4-dioxo-6-vinylctahydroquinazolin-4a (2H) -yl) acetamide.

To a solution of rac- (2R, 4R) -2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylic acid (1.26 g,

4.06 mmol, 1 equiv.) In benzene (50 mL) N, N-diisopropylethylamine (2.1 mL, 12.18 mmol, 3 equiv.) And diphenylphosphoryl azide (1.75 mL, 8.12 mmol) were added , 2 equiv.). The mixture was refluxed for 6.5 h. The reaction was quenched with 2N HCl. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran-H2O (15 ml: 15 ml) and stirred at room temperature for 2 h. Then 12N HCl (5 mL) was added and stirred for 3 h. The solvent was evaporated in vacuo. The aqueous layers were extracted with DCM twice. The organic layer was washed with 1M NaOH, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (hexane / AcOEt, 3: 1) to provide the corresponding product as a single diastereoisomer (760 mg, 61%, white solid). ESI + MS: m / z = 308.2 (M + 1) +; ES IM S: m / z = 306, 2 (M -1) -. 1H RM N (700 MH z, C lo ro fo rm o -d) 5 7.16 (s, 1H), 5.75 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H) , 5.15 (s, 1H), 5.08-4.97 (m, 2H), 3.46 (dt, J = 13.0, 4.0 Hz, 1H), 2.97-2, 83 (m, 2H), 2.52 (s, 3H), 2.36-2.27 (m, 1H), 1.97 (dtt, J = 13.4, 4.0, 1.8 Hz, 1H ), 1.85 (dtd, J = 12.3, 4.5, 2.3 Hz, 1H), 1.33 (s, 9H), 1.32-1.26 (m, 1H).

Step C. rac-N - ((4aR, 6R) -3- (-Butyl) -2,4-dioxo-6- (2- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) ethyl) octahydroquinazolin-4a (2H) -yl) acetamide.

The title compound was obtained in the same way as in Example 26, step B, using rac-N - ((4aR, 6R) -3- (tert-butyl) -2,4-dioxo-6-vinylctahydroquinazolin-4a (2H) -yl) acetamide (760 mg, 2.47 mmol, 1 equiv.), Dppe (59 mg, 0.148 mmol,

0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (50 mg, 0.074 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1,3,2 -dioxaborolane (466 ^ L, 0.25 mmol, 1.3 equiv.) and DCM (20 mL). The crude product was purified by silica gel column chromatography (DCM / MeOH 100: 1 to 50: 1) to provide the corresponding product (590 mg, 55%, white solid). ESI + MS: m / z = 436.3 (M + 1) +; ESI-MS: m / z = 434.2 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 57.16 (s, 1H), 4.99 (s, 1H), 3.43 ( dd, J = 13.0, 4.1 Hz, 1H), 2.90 (d, J = 3.4 Hz, 1H), 2.87-2.79 (m, 1H), 2.51 (s , 3H), 1.98-1.92 (m, 1H), 1.82-1.77 (m, 1H), 1.54-1.52 (m, 1H), 1.44-1.38 (m, 2H), 1.31 (s, 9H), 1.26 (d, J = 1.3 Hz, 12H), 1.11 (qd, J = 12.7, 4.9 Hz, 1H) , 0.85 - 0.73 (m, 2H)

Step D. rac- (1R, 5R) -1-Acetamido-2-amino-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) ethyl) cyclohexane-1-carboxamide.

A mixture of rac-N - ((4aR, 6R) -3- (tert-butyl) -2,4-dioxo-6- (2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) ethyl) octahydroquinazolin-4a (2H) -yl) acetamide (270 mg, 0.62 mmol, 1 equiv.) and 5N NaOH (2 mL) was refluxed for 3.5 h. Then 6N HCl was added until pH = 9 and extracted with DCM three times. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the corresponding product as a mixture of epimers, dr. = 9: 1

(150 mg, 59%, colorless oil). ESI + MS: m / z = 410.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.25 (s, 1H), 6.07 (d, J = 9.9 Hz, 1H), 3.79 (ddd, J = 12.2, 9.8 , 5.3 Hz, 1H), 3.74 (q, J = 7.0 Hz, 2H), 3.70-3.62 (m, 1H), 2.24-2.17 (m, 1H) , 2.00, 1.98 [(2s, 3H, two epimers)], 1.87-1.75 (m, 1H), 1.53-1.48 (m, 1H), 1.34, 1 , 33 [(2s, 9H, two epimers)], 1.26, 1.25 [(2s, 12H, two epimers)], 1.17 (t, J = 7.4 Hz, 1H), 1.06 - 0.89 (m, 2H), 0.86-0.69 (m, 2H).

Step E. rac- (1R, 5R) -1-acetamido-N- (tert-butyl) -2- (dimethylamino) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide.

To a solution of rac- (1R, 5R) -1-acetamido-2-amino-N- (tert-butyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (96 mg, 0.23 mmol, 1 equiv.) in 1,2-dichloroethane (1.5 mL) was added formaldehyde

(0.5 mL, 6.65 mmol, 30 equiv.). The mixture was stirred at room temperature for 30 min. Then sodium triacetoxyborohydride (0.5 g, 10 equiv.) Was added and stirred overnight. The mixture was diluted with dichloromethane and washed with 5% NaHCO3. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM / MeOH 50: 1 to 20: 1) to provide the corresponding product as a mixture of epimers, dr. = 9: 1 (35 mg, 34%, colorless oil). ESI + MS: m / z = 438.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 6.71 (d, J = 9.9 Hz, 1H), 6.56 (s, 1H), 4.18 - 4.11 (m, 1H), 2 , 35 (s, 6H), 1.93, 1.91 [(2s, 3H, two epimers)], 1.78-1.69 (m, 1H), 1.65-1.61 (m, 1H ), 1.38 (s, 9H), 1.36-1.32 (m, 2H), 1.30-1.28 (m, 3H), 1.26, 1.25 [(2s, 12H, two epimers)], 0.94-0.86 (m, 2H), 0.81-0.69 (m, 2H).

Step F. Rac- (1R, 5R) -1-amino-5- (2-boronoethyl) -2- (dimethylamino) cyclohexane-1-carboxylic acid.

A mixture of rao- (1R, 5R) -1-acetamido-N- (tert-butyl) -2- (dimethylamino) -5- (2- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) ethyl) cyidohexane-1-carboxamide (35 mg, 0.08 mmol, 1 equiv.) and 6N HClac (2 mL) were heated at 160 ° C for 29h. The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as separable diastereoisomers. Overall yield: 9%.

First epimer:

Single epimer (1.6 mg, colorless film); ESI + MS: m / z = 258.0 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.83 (dd, J = 12.3, 3.7 Hz, 1H), 2.92 (s, 6H), 2.32 (ddd, J = 14.4 , 4.1, 1.9 Hz, 1H), 2.14 (dq, J = 13.6, 3.6, 3.2 Hz, 1H), 2.00-1.94 (m, 1H), 1.76 (ddq, J = 12.5, 8.2, 4.1 Hz, 1H), 1.64 (td, J = 13.0, 3.4 Hz, 1H), 1.56 (dd, J = 14.4, 12.6 Hz, 1H), 1.50 (ddt, J = 13.5, 10.8, 5.6 Hz, 1H), 1.36-1.27 (m, 1H) , 1.12-1.02 (m, 1H), 0.82 (ddd, J = 16.2, 10.4, 6.0 Hz, 1H), 0.72 (ddd, J = 15.8, 10.3, 6.1 Hz, 1H).

Second epimer:

Single epimer (0.7 mg, colorless film); ESI + MS: m / z = 258.0 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.75 (dd, J = 12.4, 3.7 Hz, 1H), 2.78 (s, 6H), 2.25 (ddd, J = 14.4 , 4.0, 2.0 Hz, 1H), 2.15-2.07 (m, 1H), 2.00-1.90 (m, 1H), 1.73 (ddq, J = 12.4 , 8.1,4.0 Hz, 1H), 1.63 (qd, J = 13.3, 3.5 Hz, 1H), 1.54-1.43 (m, 2H), 1.31 ( dddd, J = 13.8, 10.1, 8.0, 6.1 Hz, 1H), 1.06 (qd, J = 13.3, 3.7 Hz, 1H), 0.80 (ddd, J = 16.2, 10.5, 6.2 Hz, 1H), 0.72 (ddd, J = 15.7, 10.3, 6.2 Hz, 1H).

Comparative Example 65. 1-Amino-3- (2-boronoethyl) -5- (dimethylamino) cyclohexane-1-carboxylic acid dihydrochloride.

Step A. 1-Acetamido-N- (tert-butyl) -3- (dimethylamino) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl ) cyclohexane-1-carboxamide.

To a solution of (3-acetamido-3- (tert-butylcarbamoyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) carbamate of tert-butyl (Ex. 56, step D; 80 mg, 0.157 mmol, 1 equiv.) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1.5 h. The solvents were evaporated in vacuo. The residue was dissolved in 1,2-dichloroethane (1 mL) and formaldehydeac (50 L, 0.627 mmol,

4 equiv.) And stirred at room temperature for 1h. Then, sodium triacetoxyborohydride (132 mg, 0.627 mmol, 4 equiv.) Was added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with 5% NaHCO3. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in methanol-dioxane

(2 mL- 70 ^ L) and formaldehydeac (70 ^ L, 0.942 mmol, 6 equiv.) And sodium cyanoborohydride (10 mg, 0.330 mmol, 2.1 equiv.) Were added. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved in chloroform (150 µL) and triethylsilane (150 µL, 0.942 mmol, 6 equiv.) And trifluoroacetic acid (150 µL) were added. The resulting mixture was stirred at 60 ° C for 7 h. The solvent was evaporated in vacuo and purified by silica gel column chromatography (DCM / MeOH 60: 1 to 1: 1) to provide the product corresponding as a mixture of diastereoisomers, dr. = 9: 1 (60 mg, 70%, white foam). ESI + MS: m / z = 438.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 68.97-8.90 [(2s, 1H, two diastereoisomers)], 6.03, 5.98 [(2s, 1H, two diastereoisomers)],), 3, 32-3.23 (m, 1H), 2.92 (d, J = 15.7 Hz, 1H), 2.89-2.82 (m, 6H), 2.80-2.56 (m, 2H), 2.20-2.14 (m, 1H), 2.12-2.10 (m, 1H), 2.02, 2.01 [(2s, 3H, two diastereoisomers)], 2.01 - 1.99 (m, 1H), 1.64-1.51 (m, 1H), 1.49-1.36 (m, 2H), 1.32, 1.31 [(2s, 9H, two diastereoisomers)], 1.25, 1.24 [(2s, 12H, two diastereoisomers)], 0.84-0.74 (m, 2H).

The second mixture of diastereoisomers was obtained in the same way as in Comparative Example 56, step H, using (3-acetamido-3- (tert-butylcarbamoyl) -5- (2- (4,4,5,5 tert-Butyl-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexyl) carbamate (80 mg, 0.157 mmol, 1 equiv.), trifluoroacetic acid (2 mL), dichloromethane

(6 mL), formaldehydeac (50 pL, 0.627 mmol, 4 equiv.), 1,2-dichloroethane (2 mL), sodium triacetoxyborohydride (130 mg, 0.627 mmol, 4 equiv.). The crude product was purified by silica gel column chromatography (DCM / MeOH 50: 1 to 1: 1) to provide the corresponding product (40 mg, 58%, white solid). ESI + MS: m / z = 438.2 (M + 1) +.

Step B. 1-Amino-3- (2-boronoethyl) -5- (dimethylamino) cyclohexane-1-carboxylic acid dihydrochloride.

The title compound was obtained in the same way as in Example 26, step C, using 1-acetamido-N- (fercbutyl) -3- (dimethylamino) -5- (2- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (60 mg, 0.137 mmol,

1 equiv.) And 6N HClac (4 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a mixture of diastereoisomers, dr = 4: 1 (5.5 mg, 12%, colorless film). It is I + Ms: m / z = 259.0 (M + 1) +; ESI-MS: m / z = 257.0 (M-1) -. 1H NMR (700 MHz, Deuterium Oxide) 63.92 - 3.41 (m, 1H, two diastereoisomers), 2.83 (d, J = 8.1 Hz, 6H), 2.57 - 2.17 ( m, 2h, two diastereoisomers), 2.05-1.90 (m, 2H, two diastereoisomers), 1.80-1.57 (m, 3H, two diastereoisomers), 1.46-1.33 (m, 2H, two diastereoisomers), 0.77-0.66 (m, 2H).

The second mixture of diastereoisomers was obtained in the same way starting from: 1-acetamido-N- (fercbutyl) -3- (dimethylamino) -5- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (20 mg, 0.04 mmol, 1 equiv.) And 6N HClac (2 mL). The residue was purified by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) and then by preparative HPLC (0.1-1% MeCN in water) to provide (after acidification with HCl 6N and subsequent lyophilization) the corresponding product as a mixture of diastereoisomers, dr = 9: 1, (1.5 mg, 5%, colorless film). ESI + m S: m / z = 259.0 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 63.62-3.43 (m, 1H), 2.85 (s, 3H), 2.84-2.81 (m, 1H), 2.80 (s , 3H), 2.66-2.59 (m, 1H), 2.28 (dt, J = 16.0, 2.5 Hz, 1H), 2.23-2.15 (m, 1H), 1.97-1.90 (m, 1H), 1.76-1.55 (m, 1H), 1.38-1.30 (m, 3H), 0.77-0.70 (m, 2H ).

Comparative Example 66. 1-Amino-2- (aminomethyl) -4- (2-boronoethyl) cidopentane-1-carboxylic acid dihydrodoride.

Step A. Methyl 2 - ((((Benzyloxy) carbonyl) amino) methyl) pent-4-enoate.

To a solution of methyl 3 - ([(benzyloxy) carbonyl] amino) propanoate (8 g, 33.71 mmol, 1 equiv.) In tetrahydrofuran

(100 mL) under argon at -78 ° C, lithium diisopropylamide (2.0 M solution in THF / heptane / ethylbenzene) (37 mL, 74.17 mmol, 2.1 equiv.) Was added dropwise. The reaction mixture was stirred for 30 min and a solution of allyl bromide (3.2 mL, 37.08 mmol, 1.1 equiv.) In tetrahydrofuran (40 mL) was added dropwise at -78 ° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (hexane / AcOEt 20: 1 to 8: 1) to provide the corresponding product (8.79 g, 94%, yellow oil). ESI + MS: m / z = 300.0 (M + 23) +.

1H NMR (700 MHz, Chloroform-d) 57.44 - 7.30 (m, 5H), 5.77 (ddt, J = 17.1, 10.0, 7.0 Hz, 1H), 5.10 (dtt, J = 17.0, 11.4, 6.7 Hz, 4H), 4.72 (d, J = 6.0 Hz, 1H), 3.70 (s, 3H), 3.49 - 3.44 (m, 1H), 3.35 (ddd, J = 14.1, 8.5, 5.8 Hz, 1H), 2.75 (dq, J = 8.7, 2.7 Hz, 1H), 2.42 (dt, J = 14.1.6.9 Hz, 1H), 2.31

(dt, J = 14.3, 7.1 Hz, 1H).

Step B. 2 - ((((benzyloxy) carbonyl) amino) methyl) pent-4-enoic acid.

The title compound was obtained in the same way as in Example 48, step B, using

Methyl 2 - ((((benzyloxy) carbonyl) amino) methyl) pent-4-enoate (8.79 g, 31.7 mmol, 1 equiv.), 1M NaOH (30 mL) and MeOH (90 mL). Corresponding product obtained (8 g, 96%, white solid). The product was used in the next step without further purification. ESI + MS: m / z = 264.0 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.41 - 7.30 (m, 5H), 5.80 (ddd, J = 17.1, 10.0, 7.2 Hz, 1H), 5.25 -5.04 (m, 5H), 3.51 (ddd, J = 14.0, 6.9, 4.4 Hz, 1H), 3.35 (ddd, J = 14.2, 8.3, 5.8 Hz, 1H), 2.85-2.70 (m, 1H), 2.53-2.40 (m, 1H), 2.40-2.30 (m, 1H).

Step C. Benzyl (2- (Methoxy (methyl) carbamoyl) pent-4-en-1-yl) carbamate.

The title compound was obtained in the same way as in Example 48, step C, using acid

2 - ((((benzyloxy) carbonyl) amino) methyl) pent-4-enoic (8.0 g, 30.38 mmol, 1 equiv), N, N-diisopropylethylamine (11 mL, 63.81 mmol, 2, 1 equiv.), N, 0-dimethylhydroxylamine hydrochloride (3.2 g, 31.90 mmol, 1.05 equiv.), HATU (12.2 g, 31.90 mmol,

1.05 equiv.) And dichloromethane (90 mL). The residue was purified by silica gel flash chromatography (hexane / AcOEt 15: 1 to 1: 1) to provide the corresponding product (7.42 g, 80%, yellow oil). ESI + MS: m / z = 307.0 (M + 1) +.

1H NMR (700 MHz, Chloroform-d) 57.42 - 7.29 (m, 5H), 5.77 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H), 5.32 (br s, 1H), 5.15 -4.99 (m, 4H), 3.59 (d, J = 8.5 Hz, 3H), 3.46-3.38 (m, 1H), 3 , 38-3.27 (m, 1H), 3.24 (br s, 1H), 3.16 (dd, J = 6.6, 3.6 Hz, 3H), 2.35 (ddt, J = 13.9, 6.9, 3.9 Hz, 1H), 2.23 (dt, J = 14.2, 6.8 Hz, 1H).

Step D. Benzyl (2-Allyl-3-oxopent-4-en-1-yl) carbamate.

The title compound was obtained in the same way as in Example 48, step D, using

Benzyl (2- (methoxy (methyl) carbamoyl) pent-4-en-1-yl) carbamate (6.56 g, 21.44 mmol, 1 equiv), vinylmagnesium bromide

(1M in THF) (100 mL, 100.7 mmol, 4.7 equiv.) And THF (130 mL). The residue was purified by silica gel flash chromatography (hexane / AcOEt 10: 1 to 4: 1) to provide the corresponding product (2.1 g, 36%, yellow oil).

ESI + MS: m / z = 274.0 (M + 1) +. 1H NMR (700MHz, Chloroform-d) 57.41-7.31 (m, 5H), 6.49-6.20 (m, 1H), 5.88-5.69 (m, 1H), 5 , 13 -5.05 (m, 7H), 4.18 (dddd, J = 13.2, 6.4, 4.9, 2.0 Hz, 1H), 2.51 (d, J = 31, 3 Hz, 1H), 2.40 (dt, J = 13.9, 6.9 Hz, 1H), 2.24 (dd, J = 14.4, 7.3 Hz, 1H), 2.13 - 2.05 (m, 1H).

Step E. Benzyl ((2-Oxocyclopent-3-en-1-yl) methyl) carbamate.

The title compound was obtained in the same way as in Example 48, step E, using benzyl (2-allyl-3-oxopent-4-en-1-yl) carbamate (2.1 g, 7.68 mmol , 1 equiv), Grubbs Catalyst, 2nd Generation (0.32 g, 0.38 mmol, 0.05 equiv.) And dichloromethane (413 mL). The residue was purified by silica gel flash chromatography (hexane / AcOEt 10: 1 to 3: 1) to provide the corresponding product (0.32 g, 17%, yellow oil). ESI + MS: m / z = 245.0 (M + 1) +.

1H NMR (700 MHz, Chloroform-d) 57.79 - 7.71 (m, 1H), 7.40 - 7.32 (m, 5H), 6.20 (dt, J = 5.8, 2, 1 Hz, 1H), 5.35 (br s, 1H), 5.12

(s, 2H), 3.63 (dt, J = 12.0, 5.7 Hz, 1H), 3.37 (dt, J = 13.0, 6.4 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.57-2.51 (m, 2H).

Step F. Benzyl ((2-Oxocyclopent-3-en-1-yl) methyl) carbamate.

The title compound was obtained in the same way as in step B from the synthesis of intermediate 1, using benzyl ((2-oxocyclopent-3-en-1-yl) methyl) carbamate (320 mg, 1, 30 mmol, 1 equiv.), 1M vinylmagnesium bromide in THF (4.6 mL, 4.57 mmol, 3.5 equiv.), HMPA (0.91 mL, 5.22 mmol, 4 equiv.), Complex copper (I) bromide dimethyl sulfide (40 mg, 0.20 mmol, 0.15 equiv.), trimethylsilyl chloride (0.83 mL, 6.52 mmol, 5 equiv.) and THF (10 mL) . The residue was purified by silica gel flash chromatography (hexane / AcOEt, 10: 1 to 8: 1) to provide the corresponding product as a mixture of diastereoisomers, dr. = 4: 1, (307 mg, 86%, colorless oil). ESI + MS: m / z = 274.0 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 57.41-7.31 (m, 5H), 5.94 -5.78 (m, 1H), 5.34, 5.29 [(2s, 1H, two diastereoisomers)], 5.13-5.05 (m, 4H), 3.51 (dq, J = 13.7, 7.9, 6.7 Hz, 1H), 3.30 (ddt, J = 26 , 3.13.4, 6.3 Hz, 1H), 3.02-2.74 (m, 1H, two diastereoisomers), 2.60-2.24 (m, 3H), 2.12-1, 91 (m, 2H).

Step F. Benzyl ((2-Acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) methyl) carbamate.

The title compound was obtained in the same way as in step C from the synthesis of intermediate 1, using benzyl ((2-oxocyclopent-3-en-1-yl) methyl) carbamate (300 mg, 1, 10 mmol, 1 equiv.), Ammonium acetate (338 mg,

4.39 mmol, 4 equiv.), Tert-butylisocyanide (250 µL, 2.20 mmol, 2 equiv.) And 2,2,2-trifluoroethanol (4.5 mL) as a solvent. The residue was purified by silica gel flash chromatography (hexane / AcOEt 10: 1 to 1: 1) to provide the corresponding product as a mixture of diastereoisomers. Overall yield: 80%. The diastereoisomers were partially separated as the following diastereoisomeric ratios:

Single diastereoisomer (66 mg, colorless oil); ESI + MS: m / z = 416.2 (M + 1) +; ESI-MS: m / z = 414.2 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 57.39-7.30 (m, 5H), 7.07 (br s, 1H) , 6.63 (br s, 1H), 5.75 (ddd, J = 17.2, 10.2, 7.1 Hz, 1H), 5.35 (br s, 1H), 5.14 -5 .08 (m, 2H), 5.03-4.90 (m, 2H), 3.40-3.29 (m, 2H), 2.96-2.88 (m, 1H), 2.74 - 2.64 (m, 1H), 2.39

(d, J = 8.6 Hz, 2H), 2.04-2.00 (m, 1H), 1.99 (s, 3H), 1.46-1.38 (m, 1H), 1, 30 (s, 9H).

Mixture of diastereoisomers (dr = 3: 1) (219 mg, colorless oil); ESI + MS: m / z = 416.2 (M + 1) +; ESI-MS: m / z = 414.2 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 57.39-7.31 (m, 5H), 7.14-6.92 (m , 1H, two diastereoisomers), 6.63, 6.45 [(2s, 1H, two diastereoisomers)], 5.85 -5.71 (m, 1H), 5.49, 5.34 [(2s, 1H, two diastereoisomers)], 5.20-5.07 (m, 2H), 5.05-4.87 (m, 2H), 3.50-3.17 (m, 2H), 3.06-2.85 (m, 1H), 2.80-2.65 (m, 1H, two diastereoisomers), 2.40-2.29 (m, 1H, two diastereoisomers), 2.03, 1.99 (2s, 3H, two diastereoisomers), 2.02-2.02 (m, 1H), 1.86-1.68 (m, 2H), 1.30, 1.29 [(2s, 9H, two diastereoisomers).

Mixture of diastereoisomers (dr = 9: 1) (83 mg, colorless oil); ESI + MS: m / z = 416.2 (M + 1) +; ESI-MS: m / z = 414.2 (M-1) -. 1H NMR (700 MHz, Chloroform-d) 7.40 - 7.31 (m, 5H), 6.43 (s, 1H), 6.38 (s, 1H), 5.90 -5.75 ( m, 1H, two diastereoisomers), 5.50 -5.40 [(2s, 1H, two diastereoisomers)], 5.19-4.91 (m, 4H), 3.37-3.20 (m, 2H ), 2.86-2.72 (m, 1H), 2.53-2.50 (m, 1H), 2.39-2.28 (m, 2H), 2.09 (dt, J = 13 , 7.2 Hz, 1H), 2.03, 2.00 [(2s, 3H, two diastereoisomers)], 1.53-1.42 (m, 1H), 1.34, 1.29 [ (2s, 9H, two diastereoisomers)].

Step G. ((2-Acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) methyl ) benzyl carbamate.

The title compound was obtained in the same manner as in Example 26, step B, using benzyl ((2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcidopentyl) methyl) carbamate (66 mg, 0.159 mmol, 1 equiv .), dppe (4 mg, 0.0095 mmol, 0.06 equiv.), bis (1,5-cyclooctadiene) diiridium (I) dichloride (3.2 mg, 0.0048 mmol, 0.03 equiv. ), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37 mL, 0.09 mmol, 1.5 equiv.) And DCM (3 mL). The crude product was purified by silica gel column chromatography (DCM / MeOH 30: 1 to 9: 1) to provide the corresponding product as a single diastereoisomer.

(106 mg, 100%, colorless oil). ESI + MS: m / z = 544.4 (M + 1) +. 1H NMR (700 MHz, Chloroform-cQ 57.41 - 7.27 (m, 5H), 7.07 (br s, 1H), 6.50 (br s, 1H), 5.12-4.97 ( m, 2H), 3.40-3.13 (m, 2H), 2.88-2.77 (m, 1H), 2.27 (dd, J = 14.4, 9.0 Hz, 1H) , 2.21-2.14 (m, 1H), 1.97 (s, 3H), 1.95-1.84 (m, 3H), 1.50-1.32 (m, 2H), 1 , 27 (s, 9H), 1.23 (s, 12H), 1.18-1.03 (m, 1H), 0.78-0.63 (m, 2H).

The second mixture of diastereoisomers was obtained in the same way starting from: benzyl ((2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) methyl) carbamate (dr = 3: 1) (222 mg, 0.53 mmol, 1 equiv.), Dppe (13 mg,

0.032 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (11 mg, 0.016 mmol, 0.03 equiv.), 4,4,5,5-tetramethyl-1, 3,2-dioxaborolane (125 mL, 0.80 mmol, 1.5 equiv.) And DCM (5 mL). The crude product was purified by silica gel column chromatography (hexane / AcOEt 10: 1 to 2: 1) to provide the corresponding product as a mixture of diastereoisomers, dr. = 3: 2, (200 mg, 69%, white foam). ESI + m S: m / z = 544.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-C) 57.41-7.29 (m, 5H), 7.11-6.91 (m, 1H), 6.52, 6.20 [(2s, 1H, two diastereoisomers)], 5.68-5.29 (m, 1H), 5.18-5.05 (m, 2H), 3.50-3.30 (m, 1H), 3.30-3.18 (m, 1H), 3.02-2.88 (m, 1H), 2.89-2.80 (m, 1H), 2.33-2.09 (m, 1H), 2.01.1 , 99 [(2s, 3H, two diastereoisomers)], 1.97-1.76 (m, 1H), 1.66-1.39 (m, 4H), 1.30, 1.29 [(2s, 9H, two diastereoisomers)], 1.25, 1.24 [(2s, 12H, two diastereoisomers)], 0.80-0.70 (m, 2H).

The third mixture of diastereoisomers was obtained in the same way starting from: benzyl (((2-acetamido-2- (tert-butylcarbamoyl) -4-vinylcyclopentyl) methyl) carbamate (dr = 9: 1) (70 mg, 0, 19 mmol, 1 equiv.), Dppe (5 mg,

0.0115 mmol, 0.06 equiv.), Bis (1,5-cyclooctadiene) diiridium (I) dichloride (4 mg, 0.0057 mmol, 0.03 equiv.), 4.4.5.5- tetramethyl-1,3,2-dioxaborolane (45 mL, 0.29 mmol, 1.5 equiv.) and DCM (3 mL). The crude product was purified by silica gel column chromatography (DCM / MeOH 100: 1 to 50: 1) to provide the corresponding product as a mixture of diastereoisomers, dr. = 9: 1, (66 mg, 64%, colorless oil). ESI + MS: m / z = 544.2 (M + 1) +. 1H NMR (700 MHz, Chloroform-C) 57.40 - 7.30 (m, 5H), 6.56 (s, 1H), 6.33, 6.19 [(2s, 1H, two diastereoisomers)], 5.64, 5.43 [(2s, 1H, two diastereoisomers)], 5.19-4.98 (m, 2H), 3.39-3.28 (m, 1H), 3.27-3, 13 (m, 1H), 3.03-2.31 (m, 1H, two diastereoisomers), 2.23-2.17 (m, 1H), 2.14-2.02 (m, 1H), 2 .01, 1.99 [(2s, 3H, two diastereoisomers)], 1.54-1.42 (m, 2H), 1.34, 1.33 [(2s, 9H, two diastereoisomers)], 1, 30-1.26 (m, 3H), 1.25, 1.24 [(2s, 12H, two diastereoisomers)], 0.83-0.68 (m, 2H).

Step H. 1-Amino-2- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid dihydrochloride.

The title compound was obtained in the same way as in Example 26, step C, using ((2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1, Benzyl 3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) methyl) carbamate (18 mg,

0.033 mmol, 1 equiv.) And 6N HClac (5 mL). The residue was purified by preparative HPLC (0.1-1% MeCN in water) and then by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with HCl 2N and subsequent lyophilization) the corresponding product as a single diastereoisomer. (2.1 mg, 21%, white foam). ESI + MS: m / z = 231.0 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.16 (dd, J = 12.7, 4.4 Hz, 1H), 2.92 (dd, J = 12.7, 11.0 Hz, 1H), 2.76-2.70 (m, 1H), 2.64 (ddt, J = 14.0, 9.1, 2.8 Hz, 1H), 2.26 (dt, J = 12.4, 6 , 2Hz, 1H), 2.14-2.06 (m, 1H), 1.54-1.42 (m, 3H), 1.23 (td, J = 12.7, 11.4 Hz, 1H), 0.77-0.71 (m, 2H).

The second mixture of diastereoisomers was obtained in the same way starting from: ((2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3, Benzyl 2-dioxaborolan-2-yl) ethyl) cyclopentyl) methyl) carbamate (50 mg,

0.092 mmol, 1 equiv.) And 6N HClac (10 mL). The residue was purified by preparative HPLC (0.1-1% MeCN in water) and then by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with HCl 2N and subsequent lyophilization) the corresponding product as a mixture of diastereoisomers, dr = 1: 1, (10.2 mg, 37%, white foam). ESI + MS: m / z = 231.0 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.21 - 3.05 (m, 1H, two diastereoisomers), 2.96 - 2.87 (m, 1H), 2.87 - 2.69 (m, 1H, two diastereoisomers) , 2.67-1.97 (m, 1H, two diastereoisomers), 2.29-1.87 (m, 1H, two diastereoisomers), 2.20-2.15 (m, 1H), 2.12- 1.75 (m, 1H, two diastereoisomers), 1.57-1.16 (m, 3H), 0.77-0.69 (m, 2H).

The third mixture of diastereoisomers was obtained in the same way starting from: ((2-acetamido-2- (fercbutylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2- benzyl dioxaborolan-2-yl) ethyl) cyclopentyl) methyl) carbamate, dr = 9: 1 (33 mg, 0.061 mmol, 1 equiv.) and 6N HClac (5 mL). The residue was purified by preparative HPLC (0.1-1% MeCN in water) and then by flash chromatography on a DOWEX® ion exchange resin (eluent, 0.1N ammonia in water) to provide (after acidification with HCl 2N and subsequent lyophilization) the corresponding product as a single diastereoisomer (1.5 mg, 8%, white solid). ESI + MS: m / z = 231.05 (M + 1) +. 1H NMR (700 MHz, Deuterium Oxide) 53.18 (dd, J = 12.7, 3.6 Hz, 1H), 2.89 (t, J = 12.0 Hz, 1H), 2.46 - 2.40 (m, 1H), 2.23-2.14 (m, 1H), 2.14-2.01 (m, 3H), 1.45-1.37 (m, 2H),

1.33-1.21 (m, 1H), 0.71-0.61 (m, 2H).

Comparative Example 67. 1-amino-4- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclopentane-1-carboxylic acid.

Step A. 1-Acetamido-N- (tert-butyl) -2 - ((dimethylamino) methyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) ethyl) cyclopentane-1-carboxamide.

A ((2-acetamido-2- (tert-butylcarbamoyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentyl) methyl) carbamate of benzyl, dr = 9: 1, (33 mg, 0.061 mmol, 1 equiv.) in MeOH (2 mL) 3 drops of 6N HCl were added and the reaction mixture was degassed, then 25 mg of Pd / C were added (10%, wet). The mixture was degassed, charged with H2, and stirred overnight. The mixture was filtered through a pad of Celite, washed with methanol (2 x 10 mL), the filtrate was concentrated in vacuo to provide the product as a colorless oil (27 mg, 99.8%). ESI + MS: m / z = 410.0 (M + 1) +. The crude product (27 mg, 0.061 mmol, 1 equiv.) Was dissolved in 1,2-dichloroethane (1 mL) and formalin (18 L, 0.24 mmol, 4 equiv.) Was added. The mixture was stirred at room temperature for 1 hr. Then, sodium triacetoxyborohydride (52 mg, 0.24 mmol, 4 equiv.) Was added to the reaction mixture and stirred at room temperature overnight. The mixture was diluted with DCM (10 mL) and quenched by adding 1M NaOH (5 mL). The product was extracted with dichloromethane (2 x 10 mL). The combined organic phases were dried over MgSO4, filtered, concentrated in vacuo and 15 mg (57%) of the crude product were obtained as a colorless oil. It was used for the next stage. ESI + MS: m / z = 438.05 (M + 1) +.

Step B. 1-Amino-4- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclopentane-1-carboxylic acid.

The title compound was obtained in the same way as Comparative Example 1, step C, using 1 Acetamido-N- (tert-butyl) -2 - ((dimethylamino) methyl) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cyclopentane -1carboxamide (15 mg, 0.19 mimols, 1 equiv.) And 6 N HClac (5 mL). The residue was purified by preparative HPLC (0.1-1% MeCN in water) and then by flash chromatography on a DOWEX® 50WX8 ion exchange resin (eluent 0.1N ammonia in water) to provide a product desired as a white solid (1.2 mg, 14%). ESI + MS: m / z = 259.0 (M + 1) +.

Comparative Example 68. (5R) -2- (aminomethyl) -5- (2-boronoethyl) -1- (methylamino) cyclohexane-1-carboxylic acid dihydrochloride.

Step A. Benzyl ((2-Oxocyclohex-3-en-1-yl) methyl) carbamate.

To a solution of diisopropylamine (192 mL, 1.37 moles) in dry THF (1,300 mL) a solution of n-BuLi in hexane (2.5M, 550 mL, 1.37 moles) was added dropwise at -78 ° C under argon. The reaction mixture was allowed to warm to room temperature, stirred for 15 min, and cooled to -78 ° C. A 2-cycloheksen-1-one (60.5 mL,

0.624 mol) and the mixture was stirred for 1h at that temperature. Next, a solution of benzyl (tosylmethyl) carbamate (219 g, 0.686 mol) in THF (800 mL) was added dropwise and the reaction was stirred for 1.5 h at -78 ° C. The mixture was then quenched with saturated NH4Cl (150 mL) and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane / AcOEt (15: 1 to 2: 1) to provide the product (27 g, 18%) as a colorless oil. ESI + MS: m / z = 260.05 (M + 1) +, 282.05 (M + 23) +. 1H NMR (700 MHz, Chloroform-d) 57.42-7.33 (m, 5H), 7.05-6.81 (m, 1H), 5.99 (dt, J = 10.0, 2, 0 Hz, 1H), 5.17-5.04 (m, 2H), 4.70 (bs, 1H), 3.50 (ddd, J = 13.9, 7.5, 4.1 Hz, 1H ), 3.33 (ddd, J = 13.3, 7.2, 5.4 Hz, 1H), 2.55-2.34 (m, 3H), 2.15-2.06 (m, 1H ), 1.80 (tdd, J = 13.4, 9.6, 6.7 Hz, 1H).

Step B. Benzyl (((4R) -2-Oxo-4-vimlc¡dohexyl) methyl) carbamate.

Rh (cod) BF4 (52 mg, 0.127 mmol), (R) -BINAP (79 mg, 0.127 mmol), and potassium vinyl trifluoroborate (1.03 g, 7.713 mmol) were added to a 50 mL round bottom flask. ). The flask was flushed with argon several times and degassed 96% EtOH (23 mL) and trimethylamine (55 L, 0.386 mmol) were added. After stirring the resulting mixture for 10 min at room temperature, benzyl ((2-oxocidohex-3-en-1-yl) methyl) carbamate (1.00 g, 3.86 mmol) was added and the reaction mixture stirred for 2h under reflux. EtOH was evaporated. The residue was diluted with ethyl acetate (50 mL) and washed with aqueous 1M HCl (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane / AcOEt (13: 1 to 5: 1) to yield the product as a white solid (overall yield: 460 mg, 44%). [a] D = 10.8 (c = 0.250 in CHCla). ESI + MS: m / z = 288.10 (M + 1) +, 310.10 (M + 23) +

1H NMR (700 MHz, Chloroform-d) 57.38-7.28 (m, 5H), 5.78 (ddd, J = 16.9, 10.4, 6.2 Hz, 1H), 5.39 -5.29 (m, 1H), 5.05-4.98 (m, 2H), 3.37 (ddd, J = 13.9, 7.6, 3.7 Hz, 1H), 3.24 (ddd, J = 13.6, 7.7, 5.3 Hz, 1H), 2.45 (dd, J = 4.0, 2.1 Hz, 1H),

2.44-2.37 (m, 1H), 2.22-2.16 (m, 1H), 2.15-2.09 (m, 1H), 2.00-1.92 (m, 1H ), 1.60-1.55 (m, 3H), 1.43 (qd, J = 13.2, 3.6 Hz, 1H).

Stage C. ((^ R ^ -ffe / 'c-Butylcarbamoyl ^ -fN-methylacetamido ^ -vinylcyclohexy ^ methiOcarbamate of benzyl.

To the stirred solution of benzyl ((^ R ^ -oxo ^ -vinylcyclohexiOmethiOcarbamate (560 mg, 1.95 mmol) and methylammonium acetate (0.75 g, 7.80 mmol) in 2,2,2-trifluoroethanol ( 3 mL), fe / r-butyl isocyanide (0.66 mL, 5.85 mmol) was added dropwise via syringe and the resulting mixture was stirred at room temperature for 24 hours, after which time it was evaporated 2,2,2-trifluoroethanol and the residue was diluted with ethyl acetate (10 mL) and washed with water (20 mL). The water was extracted with ethyl acetate (3 x 10 mL) and the organic layer was dried over MgSO4, filtered and evaporated under reduced pressure The crude product was purified by flash chromatography on silica gel using hexane / AcOEt (20: 1 to 1: 1) to provide the product as a white solid (95 mg, 11%) .ESI + MS: m / z = 444.30 (M + 1) +, 466.30 (M + 23) +. 1H NMR (700 MHz, Chloroform-d) 57.39-7.32 ( m, 4H), 7.32 - 7.28 (m, 1H), 5.77 (ddd, J = 17.0, 10.4, 6.4 Hz, 1H), 5.13 -5.06 ( m, 2H), 5.03 (d, J = 17.2 Hz, 1H), 4, 95 (dt, J = 10.4, 1.4 Hz, 1H), 4.84 (br s, 1H), 3.56-3.29 (m, 2H), 3.01

(dt, J = 13.9, 3.8 Hz, 1H), 2.88 (s, 3H), 2.40-2.27 (m, 1H), 2.16 (s, 3H), 1, 99-1.88 (m, 1H), 1.78-1.67 (m, 1H), 1.58-1.54 (m, 1H), 1.50-1.36 (m, 2H), 1.31 (s, 9H), 1.27-1.23 (m, 2H).

Step D. (((4R) -2- (fe / 'c-But¡lcarbamo¡l) -2 - (' N-methyl acetamide) -4- (2- (4,4,5,5 Benzyl-tetramethyl-1,3,2-dioxaborolan-2-iOetiOcyclohexyOmethiOcarbamate.

A mixture of dppe (4.8 mg, 0.012 mmol) and bisO ^ -dclooctadiene ^ iiridium dichloride (4.0 mg, 0.006 mmol) in dry dichloromethane (2 mL) was purged with argon. Then, the solution of benzyl ' ((( 4R) -2- ( tert- butylcarbamoiO ^ N-methylacetamido ^ -vinylcyclohexyOmethiOcarbamate) and benzyl 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37 µl, 0.26 mmol) in DCM (2 mL) (argon purged). The reaction mixture was stirred at room temperature overnight. After that time, the reaction was diluted with DCM (10 mL), washed with 5% NaHCO3 (2 x 20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was used in the next step without further purification.

Step E. (5R) -2- (Aminomethyl) -N- (fe / 'c-butyl) -1 - (N-methylacetamido) -5- (2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide.

(((4R) -2- (fe / 'c-butylcarbamoyl) -2- (N-methylacetamido) -4- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) was dissolved Benzyl -2-yl) ethyl) cyclohexyl) methyl) carbamate (115 mg, 0.20 mmol, 1 equiv.) In 6 mL of MeOH and purged with argon. Next, 10 mg of wet 10% Pd / C and 3 drops of 6N HCl were added and the resulting mixture was stirred under hydrogen atmosphere (balloon) for 3h. Then a mixture was filtered through the Celite pad (washed several times with MeOHabs) and the solvent was evaporated. The residue was carried to the last stage without further purification.

Step F. (5R) -2- (aminomethyl) -5- (2-boronoethyl) -1- (methylamino) cyclohexane-1-carboxylic acid dihydrochloride.

(5R) -2- (aminomethyl) -N- (fe / 'c-butyl) -1- (N-methylacetamido) -5- (2- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) ethyl) cyclohexane-1-carboxamide (38 mg, 0.083 mmol) and 6N HClac (8 mL) at reflux for 6h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography on DOWEX® and then by preparative Hp LC (0.1-1% MeCN in water) to provide (after acidification with 6M HCl) the desired product as single diastereoisomers (6.2 mg, overall yield 22%).

The first diastereoisomer: 4.1 mg, white solid. ESI + MS: m / z = 259.10 (M + 1) +, 1H NMR (700 MHz, Deuterium Oxide) 53.26 (dd, J = 13.4, 10.3 Hz, 1H), 3, 02 (dd, J = 13.4, 3.9 Hz, 1H), 2.65 (s, 3H), 2.40-2.30 (m, 1H), 2.09-2.01 (m, 1H), 1.97-1.81 (m, 2H), 1.81-1.75 (m, 1H), 1.60 (dd, J = 15.8, 13.1 Hz, 1H), 1 .47 (tdd, J = 9.5, 7.9, 4.3 Hz, 2H), 1.34 (dddq, J = 16.7, 10.2, 7.1.3.8, 3.3 Hz, 1H), 1.24-1.10 (m, 1H), 0.91-0.79 (m, 2H).

The second diastereoisomer: 2.1 mg, white solid. ESI + MS: m / z = 259.05 (M + 1) +, 1H NMR (700 MHz, Deuterium Oxide) 53.29 (dd, J = 13.4, 10.6 Hz, 1H), 3, 03-2.99 (m, 1H), 2.68 (s, 3H), 2.47-2.35 (m, 1H), 2.14-2.06 (m, 1H), 1.97 - 1.81 (m, 2H), 1.81-1.72 (m, 1H), 1.64 (dd, J = 15.9, 13.1 Hz, 1H), 1.48-1.39 ( m, 2H), 1.37 (dddt, J = 13.1, 10.0, 7.0, 3.4 Hz, 1H), 1.25-1.10 (m, 1H), 0.85- 0.80 (m, 2H).

Example 69. (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid.

Step A. (1R, 2S, 5R) -1-Acetamido-N- (fe / 'c-butyl) -2 - ((ethyl (methyl) amino) methyl) -5-vinylcyclohexane-1-carboxamide.

The title compound was obtained in the same way as in Example 26, step A, using (1R, 2R, 4R) -2-acetamido-2- (fe / 'c-butylcarbamoyl) -4-vinylcyclohexane-1-carboxylate Ethyl (Intermediate 2, 0.47 g, 1.38 mmol, 1 equiv.), 1M DIBAL-H in DCM (4.28 mL, 4.28 mmol, 3.1 equiv.), glacial acetic acid (0 , 39 mL, 6.90 mmol, 5 equiv.), N-ethylmethylamine (0.24 mL, 2.76 mmol, 2 equiv.), Sodium triacetoxyborohydride (1.17 g, 5.52 mmol, 4 equiv. ). The reaction mixture was washed with KHSO41M (30 mL). The aqueous solution was then alkalized to pH 12 with the use of 1M NaOH and the product was extracted with DCM (5 x 30 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The desired product was obtained as a single diastereoisomer (239 mg, 51%, white solid). ESI + MS: m / z = 338.1 (M + 1) +. [a] ü = 42.3 (c = 0.250 in CHCh).

1H NMR (700 MHz, Chloroform-d) 5 10.47 (s, 1H), 8.28 (s, 1H), 5.72 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H), 4.97 (dt, J = 17.3, 1.5 Hz, 1H), 4.91 (d, J = 10.4 Hz, 1H), 3.51 (t, J = 11.7 Hz, 1H), 3.21 (d, J = 13.2 Hz, 1H), 2.58-2.48 (m, 1H), 2.37-2.26 (m, 1H), 2.24 (s, 3H), 2.16 (dq , J = 13.2, 3.5 Hz, 1H), 2.11-2.04 (m, 1H), 2.00 (d, J = 14.2 Hz, 1H), 1.90 (s, 3H), 1.80 (d, J = 13.2 Hz, 1H), 1.58-1.50 (m, 1H), 1.39-1.33 (m, 1H), 1.32 (s , 9H), 1.21-1.12 (m, 2H), 1.10-1.01 (m, 3H).

Step B. ((1R, 2S, 5R) -1-Acetamid-N- (fe / 'c-butyl) -2 - ((ethyl (methyl) amine) methyl ) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl) cidohexane-1-carboxamide and acid (2 - (( 1R, 3R, 4S) -3-acetaminophen-3- (fe / 'c-but¡lcarbamo¡l) -4 - ((eth¡l (methyl) am¡no) methyl) c¡ clohex¡l) et¡l) boron¡co.

The title compounds were obtained in the same manner as in Example 26, step B, using (1R, 2S, 5R) -1-acetamid-N- (fe / 'c-butyl) -2 - ((ethyl (methyl) amino) methyl) -5-v¡n¡lc¡clohexane-1-carboxam¡da (232mg, 0.69 mmol, 1 equiv. ), dppe (16mg, 41.0 emols, 0.06 equ¡v.), b¡s (1,5-cyclooctadene) d¡¡r¡d¡o (I) chloride ( 14mg, 20.5 emols, 0.03 equ¡v.), 4,4,5,5-tetramethyl-1,3,2-d¡oxaborolane (249 ^ L, 1.72 mmol, 2.5 equiv.) and DCM (12 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 1: 0 to 2: 1) to provide the corresponding products (303 mg, 95% ).

((1R, 2S, 5R) -1-acetamide-N- (fe / 'c-butyl) -2 - ((ethyl (methyl) amino) methyl) -5 - (2- (4,4,5,5) -tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) c¡dohexane-1-carboxamide: 120 mg, sticky light yellow solid. ESI + MS: m / z = 466.1 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 10.51-10.40 (m, 1H), 8.35-8.23 (m, 1H), 3.58-3.47 (m, 1H), 3.24-3.14 (m, 1H), 2.57-2.47 (m, 1H), 2.35-2.25 (m, 1H), 2.25-2.21 (m, 3H ), 2.12-2.04 (m, 1H), 2.01-1.95 (m, 1H), 1.91-1.85 (m, 3H), 1.81-1.73 (m , 1H), 1.57-1.48 (m, 1H), 1.36-1.27 (m, 11H), 1.26-1.20 (m, 15H), 1.08-1.03 (m, 3H), 1.00-0.91 (m, 1H), 0.87 (t, J = 7.2 Hz, 1H), 0.83-0.69 (m, 1H).

During purification on silica gel column chromatography, the pinacolboronate ester was partially deprotected to provide a free, acidic boron acid ( 2 - ((1R, 3R, 4S) -3-acetamide-3- (fe / -c-but¡lcarbamo¡l) -4 - ((eth¡l (methyl) am¡no) met¡ l) cyclohexyl) ethyl) boron: 183 mg, sticky light yellow solid. ESI + MS: m / z = 384.0 (M + 1) +.

Stage C. Acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyohexane-1-carboxylic.

The title compound was obtained in the same way as in Example 26, step C, using a mixture of ((1R, 2S, 5R) -1-acetamid-N- (fe / 'c-buti l) -2 - ((ethyl (methyl) amino) methyl) -5- (2- (4,4,5,5-tetramethyl-1,3,2-d¡ oxaborolan-2-¡l) ethyl) cyclohexane-1-carboxamide and acid (2 - ((1R, 3R, 4S) -3-acetamide-3- (fe / 'c- but¡lcarbamo¡l) -4 - ((et¡l (methyl) am¡no) methyl) cyclohex¡l) et¡l) boron¡co

(178 mg), 6N HClac (20 mL). The crude product was purified by preparative HPLC (0.1-1.0% MeCN in water) and then by ionic exchange resin flash chromatography. DOWEX® 50WX8 (eluent 0.1N ammonia in water) to provide (after lyophilization) a desired product as a white solid (25mg, 23%). ESI + MS: m / z = 287.1 (M + 1) +. [a] o = -41.6 (c = 0.125 in H2O). 1H NMR (700 MHz, Deuterium Oxide) 53.16 (dd, J = 13.2, 9.7 Hz, 1H), 3.04 - 2.98 (m, 1H), 2.92 - 2.82 (m, 2H), 2.63 (s, 3H), 2.11 2.06 (m, 1H), 1.91-1.83 (m, 2H), 1.74 (dq, J = 12.9, 3.7 Hz, 1H), 1.65-1.56 (m, 2H), 1.37-1.26 (m, 2H), 1.22 (t, J = 7, 2Hz, 3H), 1.09 (t, J = 12.7, 3.9Hz, 1H), 0.98 (dq, J = 12.7, 3.9Hz, 1H), 0.79 (t , J = 8.3 Hz, 2H).

Example 70. Acid (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) c¡ clohexane-1-carboxylic.

Stage A. (1R, 2S, 5R) -1-Acetamid-N- (fe / 'c-but¡l) -2- (p¡per¡d¡n-1-¡lmet¡l) -5 -v¡n¡lcyclohexane-1-carboxam¡da.

AcHN, CONHf-Bu

The title compound was obtained from the m¡sm c a m r w ay as in Example 26, Step A, using (1R, 2R, 4R) -2-acetam¡do-2- (fe / 'c-but¡ lcarbamo¡l) -4-v¡n¡lcyclohexane-1-carboxylate (Intermediate 2, 0.2 g, 0.59 mmol, 1 equiv.), 1M DIBAL-H in DCM (1.83 mL , 1.83 mmol, 3.1 equiv.), Glacial acetic acid (0.17 mL, 2.95 mmol, 5 equiv.), Piperidine (0.117 mL,

1.18 mmol, 2 equiv.), Sodium triacetoxyborohydride (0.5 g, 2.36 mmol, 4 equiv.). The crude product was purified by silica gel flash chromatography (DCM / MeOH, 70: 1 to 25: 1) to provide the corresponding product as a single diastereoisomer (0.123 g, 57%, colorless oil). ESI + MS: m / z = 364.20 (M + 1) +. [a] D = 32.1 (c = 0.250 in CHCla).

1H NMR (700 MHz, Chloroform-d) 510.45 (s, 1H), 8.26 (s, 1H), 5.74 (ddd, J = 17.1, 10.4, 6.5 Hz, 1H ), 5.07-4.85 (m, 2H), 3.46-3.19 (m, 2H), 2.69-2.55 (m, 1H), 2.39-2.24 (m , 1H), 2.26 - 2.06 (m, 2H), 1.99 (s, 3H), 1.82 (dt, J = 13.0, 2.0 Hz, 1H), 1.69 - 1.45 (m, 7H), 1.38 (dt, J = 6.7, 2.1 Hz, 2H), 1.35 (s, 9H), 1.32-1.22 (m, 2H) , 1.22-1.10 (m, 2H).

Stage B. (/ R, 2S, 5R) -1-Acetamid-N- (fe / 'c-butyl) -2- (p¡per¡d¡n-1-¡lmet¡l) -5- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l) ethyl) cyclohexane-1-carboxamide.

The title compound was obtained in the same way as in Example 26, step B, using (1R, 2S, 5R) -1-acetamid-N- (fe / 'c-butyl) -2- ( p¡per¡d¡n-1-¡lmeth¡l) -5-v¡n¡lcyclohexane-1-carboxam¡da (0.12 g, 0.33 mmol, 1 equiv.), dppe (8 mg, 0.02 mmol, 0.06 equiv.), B¡s (1,5-cyclooctadene) dichloride (I) (6.7 mg, 0.01 mmol, 0 .03 equiv.), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (77 ^ L, 0.5 mmol, 1.5 equiv.) And DCM (4 mL). The crude product was purified by silica gel column chromatography (gradient elution, DCM / MeOH 30: 1 to 10: 1) to provide the corresponding products as a colorless oil (116 mg, 71%). ESI + MS: m / z = 492.05 (M + 1) +. 1H NMR (700 MHz, Chloroform-d) 510.43 (s, 1H), 8.32 (s, 1H), 3.38 (dd, J = 13.7, 10.6 Hz, 1H), 3, 26-3.16 (m, 1H), 2.83-2.45 (m, 2H), 2.35-2.21 (m, 1H), 2.13-2.05 (m, 2H), 1.99 (d, J = 1.5Hz, 1H), 1.98 (s, 3H), 1.79 (d, J = 12.8Hz, 2H), 1.62-1.46 (m , 7H), 1.33 (s, 9H), 1.28 (d, J = 9.9Hz, 2H), 1.25 (s, 12H), 1.01-0.86 (m, 3H) , 0.86-0.70 (m, 2H).

Stage C. Acid (1 R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡per¡d¡n-1-¡lmeth¡l) cyclohexane-1 -carboxylic.

The title compound was obtained in the same way as in Example 26, step C, using (1R, 2S, 5R) -1-acetamid-N- (fe / 'c-butyl) -2- ( p¡per¡d¡n-1-¡lmeth¡l) -5- (2- (4,4,5,5-tetrameth¡l-1,3,2-d¡oxaborolan-2-¡l) ethyl ) cyclohexane-1-carboxamide (110 mg,

0.22 mmol, 1 equiv.), 6N HClac (10 mL). The crude product was purified by preparative HPLC (0.1-1% MeCN in water) and then flash chromatography on a DOWEX® 50WX8 ion exchange resin (eluent 0.1N ammonia in water) to provide (then lyophilization) a desired product as a white solid (14 mg, 20%). ESI + MS: m / z = 313.05 (M + 1) +. [a] D = 39.1 (c = 0.125 in H2O). 1H NMR (700 MHz, Deuterium Oxide) 53.17-2.60 (m, 6H), 2.00 (ddd, J = 13.0, 3.5, 1.9 Hz, 1H), 1.85 - 1.70 (m, 2H), 1.71-1.34 (m, 9H), 1.25-1.15 (m, 2H), 0.98 (t, J = 12.6 Hz, 1H ), 0.90-0.78 (m, 1H), 0.70-0.61 (m, 2H).

Example 71. Acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡rrol¡d¡n-1-¡lmet¡l) cyclohexane- 1-carboxylic.

The title compound was obtained in the same way as in Example 23 (Step A to C) but starting from the enantiomerically pure Intermediate 2. (> 99% ee). The crude product, after hydrolysis, was purified by preparative HPLC (0.1-1% MeCN in water) and then flash chromatography on a DOWEX® 50WX8 ion exchange resin (0.1N ammonia eluent in water ) to provide (after lyophilization) a desired product as a white solid (0.46 g, 53%, after step C). ESI + MS: m / z = 298.80 (M + 1) +. [a] D = -49.3 (c = 0.125 in H2O). 1H NMR (700 MHz, Deuterium Oxide) 83.18 (dd, J = 13.2, 7.5 Hz, 1H), 3.10 (d, J = 6.6 Hz, 4H), 3.00 ( dd, J = 13.2, 5.6 Hz, 1H), 1.99 (ddd, J = 12.9, 3.4, 1.9 Hz, 1H), 1.93-1.87 (m, 4H), 1.81-1.73 (m, 1H), 1.70 (qd, J = 7.7, 5.8 Hz, 1H), 1.61 (ddt, J = 10.9, 8, 1, 3.6 Hz, 2H), 1.48 (ddh, J = 12.3, 9.6, 3.2 Hz, 1H), 1.30 - 1.15 (m, 2H), 0.95 (t, J = 12.6 Hz, 1H), 0.92-0.81 (m, 1H), 0.74-0.59 (m, 2H).

Human arginase activity assay

An enzyme assay with recombinant human arginases 1 (Biolegend, Cat. No. 552502) and 2 (house in a eukaryotic CHO expression system, purified by FPLC) was used in order to evaluate the inhibitory activity of the compounds. The assay was performed in the 96-well plate format, each reaction in a total volume of 100 uL. The test is based on the measurement of urea, which is a product of the enzymatic degradation of L-arginine. (Baggio et al. J. Pharmacol. Exp. Ther. 1999, 290, 1409-1416). The colored product is developed by adding a mixture of reagent A (4 mM oPA in 50 mM boric acid in 1 M sulfuric acid, 0.03% Brij-35) and reagent B (4 mM NED in 50 mM boric acid in acid sulfuric 1 M, Brij-35 at 0.03%) in equal proportions. The absorbance of each well was measured at 530 nm.

Briefly, to each well of a 96-well microtiter plate, 40 pL of enzyme was added in the reaction assay buffer (pH 7.4, 100 mM sodium phosphate buffer, 130 mM NaCl, 1 mg / mL of albumin), 50 pL of the test compound solution and 10 pL of enzyme substrate solution (L-arginine hydrochloride, natural pH 5.6, final concentration 20 mM and a cofactor - manganese chloride, final concentration 150 pM) . For the positive control, only the enzyme and substrate were used, the negative controls contained substrate solution with assay buffer. After incubating the microtiter plate at 37 ° C for 60 min, 150 pL of mixed reagents A and B were added to each well to stop the reaction. The absorbance (A = 530 nm) was measured 20 minutes later, after color development. The production of urea in the absence of any compound was considered the maximum arginase activity. The absorbance in the absence of arginase (background) was subtracted from all values. The normalized OD was used to generate a concentration response curve by plotting percent inhibition versus log [concentration] of the compound and using regression analysis (GraphPad Prism 7.0.) To calculate IC50 values.

IC50 values were calculated using GraphPad Prism and divided into the following classes: A = 1-100 nM;

B = 100-1,000 nM; C = 1-10 pM; D = 10-100 pM; and E> 100 pM.

The inhibitory activity of the exemplary compounds according to the invention was presented in Table 1.

To illustrate the superior cellular activity of the compounds according to the invention over known arginase inhibitors, the selected compounds and Comparative Examples 1'-3 'were also tested in a cell-based assay using murine primary macrophages.

Cell-based assay

Efficacy of Selected Examples Against Intracellular Arginase in Isolated Murine Bone Marrow Macrophages - Bone Marrow Derived Macrophages (BMDM)

Background: Macrophages are the most specialized phagocytic cells and acquire a specific phenotype and function in response to a variety of external triggers as a consequence of adaptation to local tissue environmental signals. Th1 pro-inflammatory cytokines such as IL-2, IL-12, IFNy, TNFa and p, give rise to the activation of macrophages towards the so-called classical inflammatory phenotype (CAM or M1 macrophages). On the other hand, Th2 cytokines such as IL-4 and IL-13, as well as anti-inflammatory molecules such as IL-10 and TGFp, activate macrophages towards an alternative phenotype (AAM or M2 macrophages) (Murray and Wynn 2011, Nat Rev Immunol 11 (11): 723-737. Hoeksema, Stoger et al. 2012, Curr Atheroscler Rep 14 (3): 254-263). M1 / M2 macrophages use different metabolic pathways for the degradation of arginine. Macrophage preference for metabolizing arginine through nitric oxide synthase (NOS) to NO and citrulline or through arginase to ornithine and urea defines them as M1 (NOS) or M2 (arginase), respectively (Mills 2012, Crit Rev Immunol 32 (6): 463-488).

Macrophages are a dominant leukocyte population that infiltrate the tumor and play a critical role in modulating the tumor microenvironment. Tumor-associated macrophages (TAMs) have been shown to exhibit a phenotype similar to M2 macrophages and their accumulation in the tumor is correlated with poor clinical outcome (Chanmee, Ontong et al. 2014, Cancer (Basel) 6 (3) : 1670-1690).

Peritoneal macrophages or murine bone marrow derivatives comprise a convenient in vitro model that allows the differentiation of these cells into M1 or M2 macrophages and their further use for study.

Materials and methods: The test was carried out according to the modification of the modified literature protocol (Pineda-Torra I et al., Methods Mol Biol. 2015; 1339: 101-9. Mia S et al. Scand J Immunol. 2014 May; 79 (5): 305-14). The femurs and tibiae were isolated from Balb / c mice. The bones were cleaned of all adherent tissues using a sterile swab without affecting the bone structure. The bones were sterilized by immersion in 70% ethanol for 5 min and then they were washed in PBS. The sides of the bones were cut out and washed with cold sterile PBS using a 26-GS needle in a sterile tube of

50 mL with a cell strainer (Falcon ™, Cat. No. U00149), until the bone socket appeared white. The cells were then centrifuged (5 min at 500 x G, 4 ° C), washed twice with PBS and counted. Cells were seeded in Petri dishes with a density of 1 x 106 / mL and cultured in DMEM (Gibco, Cat. No. 31331 029) with FBS to 10% pen-strep to 1% and 50 ng / mL M-CSF (PeproTech, Cat. No. 315-02), (37 ° C, 5% CO2). After five days, the cells were subcultured on a P96 plate (BD, Cat. No. 353072) with a density of 64,000 cells / well in medium supplemented with 50 ng / mL of M-Cs F and 20 ng / mL of IL-4 (Biomibo Cat. No. 214 1). One day later, the exemplary compounds (dissolved in PBS) were added in several different concentrations and, 24 hours later, the urea level in each well was measured (Jung D et al., Clin Chem. 1975, 21 (8): 1136-40). The urea concentration in the absence of any compound was considered the maximum. The absorbance of the cell culture media (background) was subtracted from all values.

IC50 values were calculated using GraphPad Prism 7.0 and divided into the following classes: A = 1-100 nM; B = 100-1,000 nM; C = 1-10 ^ M; D = 10-100 ^ M; and E> 100 ^ M. For the selected Examples, the activity class for ARG2 was estimated based on% inhibition for the 1 µM and 100 µM concentrations of the tested compounds.

The inhibitory activity of the exemplary compounds according to the invention was presented in Table 1.

Table 1

It should be noted that the compound selected from the compounds of the invention showed promising in vivo efficacy in mouse and rat tumor xenograft models (CT26 colon carcinoma, B16F10 melanoma, Lewis LLC lung carcinoma, C6 brain glioma). The compound was administered orally or intraperitoneally in a dosage of 10-50 mg / kg (body weight), twice a day. The inhibition of tumor growth ranged between 31% and 53%.

Claims (22)

1. A compound represented by Formula (Ib):

where: R 'is -OH, (C1-C8) alkyl, or -NH2, wherein the alkyl is optionally substituted with -NRdRe or heterocyclyl having 3 to 7 atoms as ring members; wherein Rd and Re are each independently hydrogen, straight or branched (C1-C6) alkyl, aryl (C3-C14) optionally substituted (C1-C6) alkylene or optionally substituted (C3-C14) aryl, or a pharmaceutically acceptable tautomer, stereoisomer, racemate, salt, ester, solvate, or polymorph thereof. 2. The compound according to claim 1, having the structure of Formula (Ib-1):

The compound according to claim 1, wherein R 'is -CH2NH2, -CH2NHCH3, -CH2NHC (CH3) 3, -CH2N (CH3) 2, -CH2N (CH3) (CH2CH3), -CH2N (CH2CH3) 2, -CH2N (CH3) (CH (CH3) 2), -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2- (7-azabicyclo [2.2.1] heptyl), -CH2-morpholinyl, -CH2NCH3Bn, -CH2- (4,4-dimethylpiperidinyl), -CH2-isoindolinyl, -CH2- (4-chlorophenylpiperidinyl), -CH2 -tetrahydroisoquinolinyl, -CH2N (CH3) Ph, -CH2N (CH3) (4-CH3OC6H4) or -CH2N (CH3) (dichlorobenzyl). 4. The compound according to claim 1, wherein R 'is (C1-C4) alkyl substituted with -NRdRe or a heterocyclyl having 5 to 6 atoms as ring members; wherein Rd and Re are each independently H or straight, branched (C1-C6) alkyl. The compound according to claim 1, having the structure of Formula (Ic):

where Rd and Re are each independently selected from hydrogen, straight or branched (C1-C6) alkyl, or Rd and Re combine with the nitrogen atom to which they are attached to form a heterocyclyl having 5 to 6 atoms as ring members. 6. The compound according to claim 5, having the structure of Formula (Ic-1):

7. The compound according to claim 5, wherein -N (Rd) (Re) is -NH2, -NHCHs, -NHC (CHs) s, -N (CHs) 2, N (CHs) (CH2CHs), N (CH2CHs) 2, N (CHs) (CH ( CHs) 2), -NCHsBn, -N (CHs) (4-CHsOC6H4), -N (CHs) (dichlorobenzyl) or -N (CHs) Ph, or Rd and Re combine with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, (7-azabicyclo [2.2.1] heptyl), morpholinyl, (4,4-dimethylpiperidinyl), isoindolinyl, (4- chlorophenyl-piperidinyl) or tetrahydroisoquinolinyl. 8. The compound according to claim 5, wherein -N (Rd) (Re) is -NH2, -NHCHs, -NHC (CHs) s, -N (CHs) 2, N (CHs) (CH2CHs), N (CH2CHs) 2 or N (CHs) (CH ( CHs) 2), or Rd and Re combine with the nitrogen atom to which they are attached to form pyrrolidinyl, piperidinyl or (7-azabicyclo [2.2.1] heptyl). 9. The compound according to claim 1, wherein the compound is: 1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2- (morpholinomethyl) cyclohexane-1-carboxylic acid; 1-amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid; 1-amino-2- (aminomethyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid; 2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolin-2 (7H) -yl) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - (((2,2,2-trifluoroethyl) amino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) cyclohexanecarboxylic acid; acid 1 -am in o -5 - (2 -bo ro noe til) -2 - ((me tila m in o) me til) c ic lo he xa no ca rb oxylic; 1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) acid hexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) acidhexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (dimethylamino) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid; or 1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer, or a solvate thereof. 10. The compound according to claim 1, wherein the compound is: rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid; rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid; rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid; rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid; rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid; rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2- (morpholinomethyl) cyclohexane-1-carboxylic acid; 1-amino-2 - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid; 1-amino-2- (aminomethyl) -5- (2-boronoethyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexane-1-carboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4,4-dimethylpiperidin-1-yl) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((4- (4-chlorophenyl) piperidin-1-yl) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((3,4-dichlorobenzyl) (methyl) amino) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (isoindolin-2-ylmethyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((diethylamino) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((2,2,2-trifluoroethyl) amino) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - (((4-methoxyphenyl) (methyl) amino) methyl) cyclohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) cyclohexanecarboxylic acid; rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) cyclohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) cyclohexanecarboxylic acid; acid (5 R) -1 -am in o -5 - (2 -bo ro noe til) -2 - (2 - (p irro lid in -1-yl) e til) c ic lo hexanoca rb oxylic o ; ác ido (5 R) -1 -a m m o -5 - (2 -b o ro n o e t¡l) -2 - (2 - (d ¡m e t¡la m m o) e t¡l) d d o h e xa n o ca rb o xílco; 1,2-diammo-5- (2-boronoethyl) ddohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (hydroxymethyl) ddohexanecarboxylic acid; 1-amino-3- (2-boronoethyl) -5- (dimethylamine) cydohexane-1-carboxylic acid; acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) ddohexane-1 -carboxylic; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pipendm-1-methyl) ddohexane-1-carboxylic acid; or (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡n'ol¡dm-1-¡lmet¡l) ddohexane-1-carboxylic acid co or a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer, or a solvate thereof. 11. The compound according to revision 1, where the compound is: Rac- (1R, 2R, 5R) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid hydrochloride; Rac- (1S, 2R, 5R) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid hydrochloride; Rac- (1S, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid hydrochloride; Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid hydrochloride; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((dimethyl) methyl) ddohexane-1 hydrochloride -carboxylic; Rac- (1R, 2R, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((dimethyl) methyl) ddohexane-1 hydrochloride -carboxylic; Rac- (1S, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((dimethylamine) methyl) ddohexane dihydrochloride -1-carboxylic; 1-amino-5- (2-boronoethyl) -2- (morpholinomethyl) ddohexane-1-carboxylic acid dihydrochloride; 1-amino-2 acid d¡hydrochloride - ((benzyl (methyl) amino) methyl) -5- (2-boronoethyl) c¡dohexane-1 -carboxylic; rac- acid d¡hydrochloride (1R, 2S, 5R) -1-ammo-5- (2-boronoet¡l) -2- (p¡n'ol¡d¡n-1-¡lmet L) ddohexane-1-carboxylic; acid d¡hydrochloride (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2- (p¡n'ol¡d¡n-1-¡lmet ¡L) ddohexane-1-carboxylic acid d¡hydrochloride 1-am¡no-2- (am¡nome¡l) -5- (2-boronoeth¡l) c¡dohexane-1- carboxylic; d¡hydrochloride of the acid 1-am¡no-5- (2-boronoet¡l) -2- (2- (p¡rrol¡d¡n-1-¡l) et¡l) c¡ dohexane-1-carboxylic; rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoeth¡l) -2 - ((4,4-d¡met¡lp¡pend N-1-l) methyl) carboxylic cyclohexane; Rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2 - ((4- (4-dorofeml) p¡pend¡ n-1-l) methyl) carboxylic cyclohexane; Rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoethyl) -2 - (((3,4-d¡chlorobenz¡l) (methyl) amino) methyl) carboxylic cyclohexane; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2- (somdolm-2-methyl) ddohexanecarboxylic acid dihydrochloride; Rac- acid dihydrochloride (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((diethylamine) methyl) ddohexanecarboxylic co; Rac- acid dihydrochloride (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2- (p¡pend¡n-1-¡lmet¡l) ddohexanecarboxylic co; Rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2 - ((¡soprop¡l (methyl) am¡ not) methyl) carboxylic cyclohexane; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((tert-butylamine) methyl) ddohexanecarboxylic acid dihydrochloride co; Rac- acid dihydrochloride (1R, 2S, 5R) -2- (7-azab¡ddo [2.2.1] heptan-7-¡lmeth¡l) -1-am¡no-5- (2-boronoethyl) carboxylic cyclohexane; rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2 - ((3,4-d¡h¡dro¡soqu Nolm-2 (1H) -l) methyl) cyclohexanecarboxylic; Rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoethyl) -2 - (((2,2,2-tr¡fluoroet¡ l) amino) methyl) carboxylic cyclohexane; d ih id ro c lo ru ro de l ác ido ra c - (1 R, 2 S, 5 R) -1 -am in o -5 - (2 -bo ro noe til) -2 - (((4 - me to x ife n il) (me til) am in o) me til) c id ohexanoca rb oxylic o; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) -cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methyl (phenyl) amino) methyl) cyclohexanecarboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (1- (dimethylamino) ethyl) cyclohexanecarboxylic acid dihydrochloride; (5R) -1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid; (5R) -1-Amino-5- (2-boronoethyl) -2- (2-dimethylamino) ethyl) cyclohexanecarboxylic acid dihydrochloride; 1,2-Diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride; 1-Amino-5- (2-boronoethyl) -2- (hydroxymethyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 5R) -1-amino-5- (2-boronoethyl) -2- (dimethylamino) cyclohexane-1-carboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid dihydrochloride; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride; or (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid dihydrochloride or a solvate thereof. 12. The compound according to claim 1, wherein the compound is: 1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid; 2- (7-azabicyclo [2.2.1] heptan-7-ylmethyl) -1-amino-5- (2-boronoethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((methylamino) methyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (2- (dimethylamino) ethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2- (pyrrolidin-1-ylmethyl) cyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) cyclohexane-1-carboxylic acid; 1-amino-2- (aminomethyl) -4- (2-boronoethyl) cyclopentane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2- (2- (pyrrolidin-1-yl) ethyl) cyclohexanecarboxylic acid; 1,2-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid; 1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid; 1-amino-5- (2-boronoethyl) -2 - ((dimethylamino) methyl) cyclohexane-1-carboxylic acid; or 1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexane-1-carboxylic acid; or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof. 13. The compound according to claim 1, wherein the compound is: (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (piperidin-1-ylmethyl) cyclohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((isopropyl (methyl) amino) methyl) cyclohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((tert-butylamino) methyl) cyclohexanecarboxylic acid; acid (1 R, 2 S, 5 R) -2 - (7 -azab ic ic lo [2.2.1] hep ta n -7 - ylm e til) -1 -am in o -5 - (2 -bo ro noe til) c ic lo hexanoca rb oxylic o; ác ido (1 R, 2 S, 5 R) -1 -am ¡no -5 - (2 -bo ro noet¡l) -2 - ((d ¡met¡la m ¡no) met¡l) ddohe xa no ca rb oxylic; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((methylamine) methyl) dohexanecarboxylic acid; (5R) -1-ammo-5- (2-boronoethyl) -2- (2- (dimethyl) ethyl) dohexanecarboxylic acid; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2- (p¡n'ol¡dm-1-¡lmet¡l) ddohexane-1-carboxylic acid co; acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) amino) methyl) ddohexane-1 -carboxylic; 1-amino-2- (amnomethyl) -4- (2-boronoethyl) cdopentane-1-carboxylic acid; 1-amino-4- (2-boronoethyl) -2 - ((dimethyl) methyl) cdopentane-1-carboxylic acid; (5R) -1-ammo-5- (2-boronoethyl) -2- (2- (p¡rrol¡d¡n-1-¡l) ethyl) ddohexanecarboxylic acid; 1,2-diamino-5- (2-boronoethyl) cdohexanecarboxylic acid; Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid; Rac- (1S, 2R, 5R) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid; Rac- (1S, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid; Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid; Rac- (1R, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((dimethyl) methyl) ddohexane-1 hydrochloride -carboxylic; Rac- (1R, 2R, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((dimethyl) methyl) ddohexane-1 hydrochloride -carboxylic; Rac- (1S, 2S, 5R) -1-ammo-5- (2-boronoethyl) -2 - ((dimethylamine) methyl) ddohexane dihydrochloride -1-carboxylic; or 1-amino-5- (2-boronoethyl) -2- (p¡peridm-1-¡lmeth¡l) ddohexane-1-carboxylic acid or a pharmaceutically acceptable salt and / or solvate thereof. 14. The compound according to revision 1, where the compound is: Acid d¡hydrochloride (1R, 2S, 5R) -1-am¡no-5- (2-boronoethyl) -2- (p¡peridm-1-¡lmet¡l) ddohexanecarboxylic ; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((sopropyl (methyl) ammo) methyl) ddohexanecarboxylic acid; Acid dihydrochloride (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ('(tert-butylammo) methyl) ddohexanecarboxylic co; Acid dihydrochloride (1R, 2S, 5R) -2- (7-azab¡ddo [2.2.1] heptan-7-lmethyl) -1-amino-5- (2 -boronoethyl) carboxylic cyclohexane; (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethyl) methyl) dohexanecarboxylic acid; Acid d¡hydrochloride (1R, 2S, 5R) -1-am¡no-5- (2-boronoethyl) -2 - ((meth¡lammo) methyl) -ddohexanecarboxylic d (5R) -1-amino-5- (2-boronoethyl) -2- (2-dimethylammo) ethyl) ddohexanecarboxylic acid hydrochloride; rac- (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2- (p¡rrol¡d¡n-1-¡lmet L) cdohexane-1-carboxylic; Acid d¡hydrochloride (1R, 2S, 5R) -1-am¡no-5- (2-boronoet¡l) -2- (p¡rrol¡d¡n-1-¡lmet¡l ) cdohexane-1-carboxylic acid (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((ethyl (methyl) am No) methyl) ddohexane-1-carboxylic; 1-amino-2- (ammomethyl) -4- (2-boronoethyl) ddopentane-1-carboxylic acid dihydrochloride; 1-amino-4- (2-boronoethyl) -2 - ((dimethyl) methyl) cdopentane-1-carboxylic acid; (5R) -1-ammo-5- (2-boronoethyl) -2- (2- (p¡rrol¡d¡n-1-¡l) ethyl) ddohexanecarboxylic acid; 1,2-diamino-5- (2-boronoethyl) cyclohexanecarboxylic acid dihydrochloride; Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid hydrochloride; Rac- (1S, 2R, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxyddohexane-1-carboxylic acid hydrochloride; H ¡d roc lo ru ro del ác¡do ra c - (1 S, 2 S, 5 R) -1 -ammo -5 - (2 -bo ro noet¡l) -2 -h ¡d ro x ¡ddohe xa not -1 -ca rb oxylic; Rac- (2S, 5R) -1-amino-5- (2-boronoethyl) -2-hydroxycyclohexane-1-carboxylic acid hydrochloride; Rac- (1R, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethylamine) methyl) cyclohexane dihydrochloride -1-carboxylic; Rac- (1R, 2R, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethyl) methyl) dihydrochloride Clohexane-1-carboxylic; Rac- (1S, 2S, 5R) -1-amino-5- (2-boronoethyl) -2 - ((dimethyl) methyl) cyclohexane-1 dihydrochloride -carboxylic; or 1-amino-5- (2-boronoethyl) -2- (p¡per¡d¡n-1-¡lmeth¡l) c¡dohexane-1-carboxylic acid or a solvate thereof. 15. A pharmaceutical composition comprising a compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof; and a pharmaceutically acceptable carrier. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use in the treatment or prevention of a disease or condition selected from the group consisting of cardiovascular disorders, sexual disorders, disorders wound healing, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, lung disorders, hemolytic disorders and cancers. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use according to claim 16, wherein the autoimmune disorder is selected from the group consisting of encephalomyelitis, multiple sclerosis, syndrome antiphospholipid 1, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyradiculoneuropathy, dermatitis herpetiformis, dermatomyositis, myasthenia gravis, pemphigus, rheumatoid arthritis, stiff person syndrome, type 1 diabetes, ankylosing spondylitis, paroxysmal hemoglobinuria, paroxysmal hemoglobinuria (PNH) Severe idiopathic autoimmune hemolytic and Goodpasture syndrome. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use according to claim 16, wherein the lung disorder is selected from the group consisting of chemically induced pulmonary fibrosis, fibrosis idiopathic pulmonary disease, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and asthma. 19. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use according to claim 16, wherein the pulmonary disorder is pulmonary hypertension. 20. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use according to claim 16, wherein the hemolytic disorder is sickle cell disease. 21. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use according to claim 16, wherein the cancer is selected from the group consisting of gastric cancer, junctional cancer gastroesophageal, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, non-small cell lung carcinoma, renal cell carcinoma, prostate carcinoma, multiple myeloma, acute and chronic leukemias, T-cell lymphomas, B cells and NK cells, neuroblastoma, glioblastoma, astrocytoma, squamous cell carcinomas of the head and neck, and melanoma. The compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use according to claim 16, wherein the cancer is chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, leukemia acute myeloid, adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, brain and spinal cord tumor, Brainstem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumors of the central nervous system, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, carcinoma of unknown primary, cancer of the central nervous system, neck cancer uterine, childhood cancers, chordoma, chronic myeloproliferative disorders, colon cancer, craniopharyngioma, cut T-cell lymphoma aneus, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing's sarcoma, extracranial germ cell tumor, extrahepatic bile duct cancer, eye cancer, histiocytoma of bone, gallbladder cancer biliary, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors, germ cell tumor, extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, hairy cell leukemia, head cancer and neck, heart cancer, hepatocellular cancer, histiocytosis, langerhans cell cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, kaposi's sarcoma, kidney cancer, langerhans cell histiocytosis, laryngeal cancer , lip and oral cavity cancer, lobular carcinoma in situ, lymphoma, l AIDS-related infoma, macroglobulinemia, male breast cancer, medulloblastoma, medulloepithelioma, merkel cell carcinoma, malignant mesothelioma, occult primary metastatic squamous neck cancer, midline tract carcinoma involving the nut gene, cancer of mouth, multiple endocrine neoplasia syndrome, plasma cell neoplasm, mycosis fungoides, myeloma, chronic myeloproliferative disorder, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, non-Hodgkin's lymphoma, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, papillomatosis, paraganglioma, paranasal sinus cancer, nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors of intermediate differentiation, pineoblastoma , pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, lymphoma of the primary central nervous system, rectal cancer, renal cell cancer, cancer of the renal pelvis, ureter cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, cancer of the salivary gland, sarcoma, sezary syndrome, skin cancer, small cell lung cancer, int stinum, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, stomach cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, gestational trophoblastic tumor, unknown primary, unusual childhood cancer, urethral cancer, uterine cancer, uterine sarcoma, waldenstrom's macroglobulinemia, or wilms tumor.